U.S. patent application number 17/538394 was filed with the patent office on 2022-03-24 for farnesoid x receptor agonists and uses thereof.
The applicant listed for this patent is Metacrine, Inc.. Invention is credited to Karensa L. DOUGLAS, Steven P. GOVEK, Andiliy G. LAI, Johnny Y. NAGASAWA, Nicholas D. SMITH.
Application Number | 20220089575 17/538394 |
Document ID | / |
Family ID | 1000006000444 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220089575 |
Kind Code |
A1 |
SMITH; Nicholas D. ; et
al. |
March 24, 2022 |
FARNESOID X RECEPTOR AGONISTS AND USES THEREOF
Abstract
Described herein are compounds that are farnesoid X receptor
agonists, methods of making such compounds, pharmaceutical
compositions and medicaments comprising such compounds, and methods
of using such compounds in the treatment of conditions, diseases,
or disorders associated with farnesoid X receptor activity.
Inventors: |
SMITH; Nicholas D.; (San
Diego, CA) ; GOVEK; Steven P.; (San Diego, CA)
; NAGASAWA; Johnny Y.; (San Diego, CA) ; DOUGLAS;
Karensa L.; (San Diego, CA) ; LAI; Andiliy G.;
(San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Metacrine, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000006000444 |
Appl. No.: |
17/538394 |
Filed: |
November 30, 2021 |
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Application
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Patent Number |
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16494272 |
Sep 13, 2019 |
11236071 |
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PCT/US2018/022513 |
Mar 14, 2018 |
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17538394 |
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62563488 |
Sep 26, 2017 |
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62563502 |
Sep 26, 2017 |
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62471517 |
Mar 15, 2017 |
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62471511 |
Mar 15, 2017 |
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62471525 |
Mar 15, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 231/12 20130101;
C07D 417/12 20130101; A61K 45/06 20130101; C07D 275/02 20130101;
C07D 413/12 20130101; C07D 401/14 20130101; C07D 401/12 20130101;
C07D 403/12 20130101; C07D 417/14 20130101; C07D 277/28 20130101;
C07D 413/14 20130101; C07D 263/32 20130101; A61P 1/16 20180101;
C07D 417/04 20130101 |
International
Class: |
C07D 403/12 20060101
C07D403/12; C07D 417/12 20060101 C07D417/12; C07D 275/02 20060101
C07D275/02; C07D 413/12 20060101 C07D413/12; C07D 417/04 20060101
C07D417/04; C07D 231/12 20060101 C07D231/12; C07D 401/12 20060101
C07D401/12; C07D 277/28 20060101 C07D277/28; A61P 1/16 20060101
A61P001/16; C07D 413/14 20060101 C07D413/14; C07D 417/14 20060101
C07D417/14; C07D 263/32 20060101 C07D263/32; C07D 401/14 20060101
C07D401/14 |
Claims
1. A compound that has the structure of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof: ##STR01336##
wherein, ring A is a 5-membered heteroaryl that is oxazolyl,
thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl,
triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or
thiadiazolyl; or ring A is a 6-membered heteroaryl that is
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; or
ring A is phenyl; X.sup.1 is CH or N; R.sup.1 is H, D, halogen,
--CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, --SH,
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; X.sup.2 is CR.sup.2 or N; R.sup.2
is H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, --SH,
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; or R.sup.1 and R.sup.2 are taken
together with the intervening atoms to form a substituted or
unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2
O or S atoms in the ring; X.sup.3 is CR.sup.3 or N; R.sup.3 is H,
D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; each
X.sup.4 is independently CH or N; R.sup.4 is H, D, F, or
--CH.sub.3; R.sup.5 is H, D, F, or --CH.sub.3; or R.sup.4 and
R.sup.5 are taken together to form a bridge that is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; each R.sup.6 is independently H, D, F, --OH,
or --CH.sub.3; m is 0, 1, or 2; R.sup.7 is H, D, halogen, --CN,
--OH, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4deuteroalkyl, C.sub.1-C.sub.4deuteroalkoxy,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4fluoroalkoxy, or
C.sub.1-C.sub.4heteroalkyl; L is absent, --Y.sup.2-L.sup.1-,
-L.sup.1-Y.sup.2--, cyclopropylene, cyclobutylene or
bicyclo[1.1.1]pentylene; Y.sup.2 is absent, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.15--,
--CH.sub.2--, --CH.dbd.CH--, --C(.dbd.O)--, --C(.dbd.O)O--,
--OC(.dbd.O)--, --OC(.dbd.O)O--, --C(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)--, --OC(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)O--, --NR.sup.15C(.dbd.O)NR.sup.15--,
--NR.sup.15S(.dbd.O).sub.2--, or --NR.sup.15--; L.sup.1 is absent
or substituted or unsubstituted C.sub.1-C.sub.4alkylene; R.sup.8 is
H, D, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6deuteroalkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, or substituted or unsubstituted monocyclic
heteroaryl; R.sup.9 is H, D, F or --CH.sub.3; R.sup.1.degree. is
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl,
--CO.sub.2H, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.14,
--OC(.dbd.O)R.sup.14, --OC(.dbd.O)OR.sup.14, tetrazolyl, imidazole,
5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
--S(.dbd.O).sub.2N(R.sup.12).sub.2,
--NR.sup.15S(.dbd.O).sub.2R.sup.14,
--C(.dbd.O)NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2NR.sup.15C(.dbd.O)R.sup.14,
--CH.sub.2N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.C)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --C(.dbd.NH)NH.sub.2,
--NHC(.dbd.NH)NH.sub.2, --C(.dbd.O)NHC(.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2OH or --OP(.dbd.O)(OR.sup.15).sub.2; or R.sup.10
is -L.sup.2-L.sup.3-L.sup.4-R.sup.13; L.sup.2 is absent,
substituted or unsubstituted C.sub.1-C.sub.6alkylene, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkylene; L.sup.3
is absent, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--NR.sup.15--, --C(.dbd.O)--, --C(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)O--, --OP(.dbd.O)(OR.sup.15)O--, or
--(OCH.sub.2CH.sub.2).sub.r--, r is 1 or 2; L.sup.4 is substituted
or unsubstituted C.sub.1-C.sub.6alkylene, or substituted or
unsubstituted C.sub.1-C.sub.6heteroalkylene; R.sup.13 is H, --CN,
--OH, --N(R.sup.12).sub.2, --NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2N(R.sup.12).sub.2, -SR.sup.12,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.14, --SO.sub.3H,
--OP(.dbd.O)(OR.sup.15).sub.2, --C(.dbd.O)R.sup.14,
--OC(.dbd.O)R.sup.14, --CO.sub.2H, --CO.sub.2R.sup.14,
--OC(.dbd.O)OR.sup.14, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, or substituted or unsubstituted monocyclic heteroaryl;
R.sup.11 is H, D, F, or --CH.sub.3; or R.sup.9 and R.sup.11 are
taken together to form a bridge that is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; R.sup.14 is
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; R.sup.15 is H
or substituted or unsubstituted C.sub.1-C.sub.6alkyl; each R.sup.16
is independently H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted monocyclic C.sub.2-C.sub.6heterocycloalkyl,
substituted or unsubstituted phenyl, or substituted or
unsubstituted monocyclic heteroaryl; n is 0, 1, or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ring A is a 5-membered heteroaryl that
is thiazolyl, oxazolyl, isothiazolyl, or isoxazolyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ring A is a 5-membered heteroaryl that
is pyrazolyl, pyrrolyl, or oxadiazolyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ring A is a 5-membered heteroaryl that
is imidazolyl, triazolyl, tetrazolyl, or thiadiazolyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01337## ##STR01338##
6. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01339## The compound of claim 6,
or a pharmaceutically acceptable salt or solvate thereof, wherein:
##STR01340##
8. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01341##
9. The compound of claim 8, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01342##
10. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01343##
11. The compound of claim 10, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01344##
12. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01345##
13. The compound of claim 12, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01346##
14. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01347##
15. The compound of claim 14, or a pharmaceutically acceptable salt
or solvate thereof, wherein: ##STR01348##
16. The compound of any one of claims 1-15, or a pharmaceutically
acceptable salt or solvate thereof, wherein: L is absent, --O--,
--S--, --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2O--,
--OCH.sub.2--, --CH.sub.2NR.sup.15--, --NR.sup.15CH.sub.2--,
--CH.dbd.CH--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)O--, --C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--,
--NR.sup.15--, cyclopropylene, cyclobutylene or
bicyclo[1.1.1]pentylene.
17. The compound of any one of claims 1-15, or a pharmaceutically
acceptable salt or solvate thereof, wherein: L is absent, --O--,
--S--, --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2O--,
--OCH.sub.2--, --CH.sub.2NR.sup.15--, --NR.sup.15CH.sub.2--,
--CH.dbd.CH--, --C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--,
--NR.sup.15--, cyclopropylene, cyclobutylene or
bicyclo[1.1.1]pentylene.
18. The compound of any one of claims 1-15, or a pharmaceutically
acceptable salt or solvate thereof, wherein: L is absent or
--C.ident.C--.
19. The compound of any one of claims 1-18, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.9 is H; R.sup.11
is H; or R.sup.9 and are taken together to form a bridge that is
--CH.sub.2CH.sub.2--.
20. The compound of claim 19, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has the structure of
Formula (II), or a pharmaceutically acceptable salt or solvate
thereof: ##STR01349##
21. The compound of any one of claims 1-20, or a pharmaceutically
acceptable salt or solvate thereof, wherein: L is absent.
22. The compound of claim 21, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has the structure of
Formula (III), or a pharmaceutically acceptable salt or solvate
thereof: ##STR01350##
23. The compound of any one of claims 1-22, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.4 is H; R.sup.5
is H; or R.sup.4 and R.sup.5 are taken together to form a bridge
that is --CH.sub.2CH.sub.2--.
24. The compound of claim 23, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has the structure of
Formula (IV), or a pharmaceutically acceptable salt or solvate
thereof: ##STR01351##
25. The compound of claim 23, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has the structure of
Formula (V), or a pharmaceutically acceptable salt or solvate
thereof: ##STR01352##
26. The compound of claim 20, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has the structure of
Formula (VII), or a pharmaceutically acceptable salt or solvate
thereof: ##STR01353##
27. The compound of claim 20, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has the structure of
Formula (VIII), or a pharmaceutically acceptable salt or solvate
thereof: ##STR01354##
28. The compound of any one of claims 1-27, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.10 is
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl,
--CO.sub.2H, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.14,
--OC(.dbd.O)R.sup.14, --OC(.dbd.O)OR.sup.14,
--NR.sup.15S(.dbd.O).sub.2R.sup.14, --CH.sub.2N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, --OC(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --S(.dbd.O).sub.2OH or
--OP(.dbd.O)(OR.sup.15).sub.2; or R.sup.10 is
-L.sup.2-L.sup.3-L.sup.4-R.sup.13; L.sup.2 is absent, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2--,
or --CH.sub.2NHCH.sub.2--; L.sup.3 is absent, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --C(.dbd.O)--,
--C(.dbd.O)NH--, --NHC(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)O--, --OC(.dbd.O)NH--, --NHC(.dbd.O)NH--,
--NHC(.dbd.O)O--, --OP(.dbd.O)(OR.sup.15)O--, or
--(OCH.sub.2CH.sub.2).sub.r--, r is 1 or 2; L.sup.4 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH.sub.2CH(OH)--, --CH(CH.sub.2OH)--, --CH(CH.sub.2OH)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(OH)CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH.sub.2OCH.sub.2--,
--CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2OCH.sub.2--,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2SCH.sub.2--,
--CH.sub.2SCH.sub.2CH.sub.2--, --CH.sub.2NHCH.sub.2-- or
--CH.sub.2NHCH.sub.2CH.sub.2--.
29. The compound of any one of claims 1-27, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.10 is
--CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14,
--OC(.dbd.O)OR.sup.14, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2, or
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2; or R.sup.10 is
-L.sup.2-L.sup.3-L.sup.4-R.sup.13; L.sup.2 is absent or
--CH.sub.2--; L.sup.3 is absent, --O--, --NH--, --C(.dbd.O)NH--,
--NHC(.dbd.O)--, --OC(.dbd.O)NH--, or --NHC(.dbd.O)O--; L.sup.4 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.2OH)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or --CH.sub.2CH(OH)CH.sub.2--.
30. The compound of any one of claims 1-29, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.13 is H, --CN,
--OH, --N(R.sup.12).sub.2, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).sub.2, --CO.sub.2H, --C(.dbd.O)NHCH.sub.3,
--OC(.dbd.O)NHCH.sub.3, NHC(.dbd.O)CH.sub.3, NHC(.dbd.O)OCH.sub.3,
NHS(.dbd.O).sub.2CH.sub.3, SO.sub.2CH.sub.3, substituted or
unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl,
substituted or unsubstituted cyclopentyl, substituted or
unsubstituted cyclohexyl, substituted or unsubstituted phenyl, or
substituted or unsubstituted monocyclic heteroaryl.
31. The compound of any one of claims 1-30, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.th is
--CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--OC(.dbd.O)R.sup.14, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14, or
--OC(.dbd.O)N(R.sup.12).sub.2.
32. The compound of any one of claims 1-31, or a pharmaceutically
acceptable salt or solvate thereof, wherein: X.sup.2 is CR.sup.2;
X.sup.3 is CR.sup.3 or N; each X.sup.4 is CH; or each X.sup.4 is N;
or one X.sup.4 is N and the other X.sup.4 is CH.
33. The compound of any one of claims 1-32, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.1 is H, D, F,
Cl, --CN, --OH, --NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)(CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --SCH(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O)CH.sub.2CH.sub.3, --S(.dbd.O)CH(CH.sub.3).sub.2,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2CH.sub.3,
--S(.dbd.O).sub.2CH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2; R.sup.2 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)(CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --SCH(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O)CH.sub.2CH.sub.3, --S(.dbd.O)CH(CH.sub.3).sub.2,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2CH.sub.3,
--S(.dbd.O).sub.2CH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2; or R.sup.1 and R.sup.2 are taken
together with the intervening atoms to form a substituted or
unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2
O or S atom in the ring that is a substituted or unsubstituted
dihydrofuranyl, substituted or unsubstituted dioxolyl, substituted
or unsubstituted furanyl, substituted or unsubstituted thienyl,
substituted or unsubstituted pyrrolyl, substituted or unsubstituted
oxazolyl, substituted or unsubstituted thiazolyl, substituted or
unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl,
substituted or unsubstituted triazolyl, substituted or
unsubstituted isoxazolyl, substituted or unsubstituted
isothiazolyl, substituted or unsubstituted dihydropyrrolyl,
substituted or unsubstituted pyridinyl, substituted or
unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl,
or substituted or unsubstituted pyridazinyl, substituted or
unsubstituted dioxinyl; R.sup.3 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)(CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, or --CH.sub.2N(CH.sub.3).sub.2.
34. The compound of any one of claims 1-32, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.1 is H, D, F,
Cl, --CN, --OH, --NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--CH.sub.3, --CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--SCH.sub.3, --CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, or --OCH.sub.2CF.sub.3; R.sup.2 is H, D, F, Cl,
--CH.sub.3, --CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--SCH.sub.3, --CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or
--OCH.sub.2CF.sub.3; R.sup.3 is H, D, F, Cl, --CH.sub.3,
--OCH.sub.3, --CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, or
--OCF.sub.3.
35. The compound of any one of claims 1-32, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.1 is --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3,
--OCH.sub.3, --SCH.sub.3, --CD.sub.3, --OCD.sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
or --OCH.sub.2CF.sub.3; R.sup.2 is H, D, F, Cl, --CH.sub.3,
--CD.sub.3, --CH.sub.2F, --CHF.sub.2, or --CF.sub.3; R.sup.3 is
H.
36. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt or solvate thereof, wherein: ##STR01355##
37. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt or solvate thereof, wherein: ##STR01356##
38. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt or solvate thereof, wherein: ##STR01357##
39. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt or solvate thereof, wherein the compound has the
structure of Formula (IX), or a pharmaceutically acceptable salt or
solvate thereof: ##STR01358##
40. The compound of any one of claims 1-39, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.8 is H, D,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CHFCH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NHCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2CH.sub.3, --C(.dbd.O)CH(CH.sub.3).sub.2,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH(CH.sub.3).sub.2, --C(.dbd.O)NHCH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2NHCH.sub.3, substituted
or unsubstituted cyclopropyl, substituted or unsubstituted
cyclobutyl, substituted or unsubstituted cyclopentyl, substituted
or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl,
substituted or unsubstituted tetrahydrofuranyl, substituted or
unsubstituted tetrahydropyranyl, or substituted or unsubstituted
tetrahydrothiopyranyl.
41. The compound of any one of claims 1-39, or a pharmaceutically
acceptable salt or solvate thereof, wherein: R.sup.8 is H,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CHFCH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NHCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted cyclopentyl, substituted or unsubstituted
cyclohexyl, substituted or unsubstituted oxetanyl, substituted or
unsubstituted tetrahydrofuranyl, or substituted or unsubstituted
tetrahydropyranyl.
42. The compound of any one of claims 1-41, or a pharmaceutically
acceptable salt or solvate thereof, wherein: each R.sup.16 is
independently is H, D, F, Cl, --CN, --OH, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --NHS(.dbd.O).sub.2CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, --C(.dbd.O)CH.sub.3,
--OC(.dbd.O)CH.sub.3, --CO.sub.2H, --CO.sub.2CH.sub.3,
--NHC(.dbd.O)CH.sub.3, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CH.dbd.CH.sub.2, --CH.ident.CHCH.sub.3,
--C.ident.CCH.sub.3, --C.ident.CCH.sub.2CH.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --SCH(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O)CH.sub.2CH.sub.3, --S(.dbd.O)CH(CH.sub.3).sub.2,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2CH.sub.3,
--S(.dbd.O).sub.2CH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, or --CH.sub.2N(CH.sub.3).sub.2, substituted
or unsubstituted cyclopropyl, substituted or unsubstituted
cyclobutyl, substituted or unsubstituted cyclopentyl, substituted
or unsubstituted cyclohexyl, substituted or unsubstituted
aziridinyl, substituted or unsubstituted azetidinyl, substituted or
unsubstituted pyrrolidinyl, substituted or unsubstituted
piperidinyl, substituted or unsubstituted tetrahydrofuranyl,
substituted or unsubstituted tetrahydropyranyl, substituted or
unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted
morpholinyl, substituted or unsubstituted thiomorpholinyl, or
substituted or unsubstituted piperazinyl.
43. The compound of any one of claims 1-41, or a pharmaceutically
acceptable salt or solvate thereof, wherein: each R.sup.16 is
independently is H, D, F, Cl, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --SCH(CH.sub.3).sub.2, --CD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
substituted or unsubstituted cyclopropyl, or substituted or
unsubstituted cyclobutyl.
44. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt or solvate thereof, wherein the compound has the
structure of Formula (X), or a pharmaceutically acceptable salt or
solvate thereof: ##STR01359##
45. A compound that is:
trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino-
)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-y-
l)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(3-fluoro-1-methy-
l-1H-indazol-5-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methyl
carbonate;
4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(3-fluoro-1-m-
ethyl-1H-indazol-5-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(3-cyclopropylisothiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-meth-
oxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-meth-
ylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphen-
yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
trans-4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(thiazo-
l-2-ylethynyl)phenyl)carbamoyl)cyclohexyl methylcarbamate;
4-(((4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(3-(thia-
zol-2-ylethynyl)phenyl)carbamoyl)cyclohexyl trans-methylcarbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methy-
lphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicy-
clo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
4-((3-(3-Cyclopropylisothiazol-5-yl)phenyl)((4-(4-methoxy-3-methylphenyl)-
bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl ethylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-
-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)-
pyridine-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bic-
yclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)trans-carbamate;
4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-y-
l)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)trans-carbamate;
4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)trans-carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
isopropylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
cyclopropylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-(dimethylamino)ethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-(dimethylamino)propyl)carbamate;
4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-
-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)trans-carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((1H-imidazol-2-yl)methyl)carbamate; tert-Butyl
(2-((((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-met-
hoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)am-
ino)ethyl)(methyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((1H-imidazol-4-yl)methyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-aminoethyl)carbamate; tert-Butyl
3-((((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)ami-
no)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
azetidin-3-ylcarbamate;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(4-(dimethylamino)butyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(5-(dimethylamino)pentyl)carbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)-
pyridine-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-(2-hydroxyethyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy ethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylthio)methyl)azetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
ethylcarbamate;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclo-
propylthiazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-
-cyclopropylthiazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(2-Isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methyl-
pyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethyla-
mino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-(((trans-4-(5-Chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)(3-(-
1-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methox-
y-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-meth-
oxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclo-
propyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-Isopr-
opyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-methoxy-5--
methylpyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-cyclo-
propyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
cis-4-(((4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H--
pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate;
trans-4-((3-(1-(tert-Butyl)-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Cyclobutyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-m-
ethylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
dimethylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-
-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
ethylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-
-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamat-
e;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4--
(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-
-isopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-
-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
ethylcarbamate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylp-
henyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylp-
yridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclo-
propyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((3-(6-(Dimethylamino)pyridine-3-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(6-Cyclopropylpyridin-3-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((3-(2-(Dimethylamino)pyrimidin-5-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclo-
propyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((6-(Dimethylamino)-[3,4'-bipyridin]-2'-yl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(6-(Dimethylamino)pyridine-3-yl)phenyl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-
-cyclopropyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-isopr-
opyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-isopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl methylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
ethylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl methyl
carbonate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(6-methoxy--
5-methylpyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)-1-methylcyclohexyl
methylcarbamate;
cis-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)-1-methylcyclohexyl
methylcarbamate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate;
4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyrid-
in-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)trans-carbamate;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((4-(2-Isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methyl-
pyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methyl-
pyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-meth-
ylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl (2-hydroxy
ethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethyla-
mino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl (2-hydroxy
ethyl)carbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-methoxyethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(1,3-dihydroxypropan-2-yl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((S)-2,3-dihydroxypropyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((R)-2,3-dihydroxypropyl)carbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl (2-hydroxy
ethyl)carbamate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methox-
y-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(1-methylazetidin-3-yl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclo-
propyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-isopr-
opyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-cyclo-
propyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(5-Chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)(3-(-
1-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
(2-hydroxy ethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
oxetan-3-ylcarbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-methoxyethyl)(methyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
thiomorpholine-4-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-
-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl (2-hydroxy
ethyl)carbamate;
trans-4-((3(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylsulfonyl)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylthio)azetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
cyclopropylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-
-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
isopropylcarbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-
-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
cyclopropylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
(2-methoxyethyl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
cyclopropylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-(methylsulfonyl)azetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
morpholine-4-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylsulfonyl)azetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylsulfonyl)azetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicy-
clo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methy-
lphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylp-
henyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylp-
yridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylp-
yridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclo-
propyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclo-
propyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-methoxyethyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
cyclopropylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
isopropylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
oxetan-3-ylcarbamate;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)-N-((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)-4-(2-(3-(methylsulfonyl)azetidin-
-1-yl)-2-oxoethyl)cyclohexanecarboxamide;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)-4-(2-((3-hydroxypropy-
l)amino)-2-oxoethyl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexy-
l)methyl)cyclohexanecarboxamide;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)-N-((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)-4-(2-((2-methoxyethyl)(methyl)am-
ino)-2-oxoethyl)cyclohexanecarboxamide;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((S)-2,3-dihydroxypropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxypropyl)(methyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-2,3-dimethylbutyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-2-methylbutyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-2-methylpropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(1-hydroxypropan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxypropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxybutan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
ethyl(2-hydroxyethyl)carbamate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylsulfonyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(2-hydroxyethoxy)azetidine-1-carboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-methylpiperazine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
piperazine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(1-methylpiperidin-4-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((R)-1-methylpiperidin-3-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-ethylpiperazine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
4-isopropylpiperazine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
2,2-dimethylmorpholine-4-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(oxetan-3-yl)azetidine-1-carboxylate;
trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-2-methylpropyl)(methyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)(methyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(3-hydroxypentan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-3-methylbutyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(1-hydroxy-2-methylpropan-2-yl)carbamate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-m-
ethylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-2-methylpropyl)carbamate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-2-methylpropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino-
)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methyl-
pyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclo-
propylthiazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-
-cyclopropylthiazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-meth-
ylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethyla-
mino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methox-
y-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate; Methyl
2-((((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)ami-
no)acetate;
2-((((trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)ami-
no)acetic acid;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclo-
propyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-isopr-
opyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-cyclo-
propyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(5-Chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)(3-(-
1-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-meth-
oxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-methoxy-5--
methylpyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methoxymethyl)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(hydroxymethyl)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
thiomorpholine-4-carboxylate 1-oxide;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
thiomorpholine-4-carboxylate 1,1-dioxide;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((dimethylamino)methyl)azetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-
-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
1-(trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-
-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) 3-methyl
azetidine-1,3-dicarboxylate;
1-(((trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)azet-
idine-3-carboxylic acid;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((tert-butoxycarbonyl)(methyl)amino)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylamino)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((tert-butoxycarbonyl)amino)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-aminoazetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-
-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate;
2-(1-(((trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)a-
zetidin-3-yl)acetic acid;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-
-isopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
isopropylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
dimethylcarbamate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
azetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-ethylazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-isopropoxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopr-
opyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-(hydroxymethyl)azetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-ethylazetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-isopropoxyazetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-isopropylazetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(hydroxymethyl)azetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-ethylazetidine-1-carboxylate;
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(hydroxymethyl)azetidine-1-carboxylate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methy-
lphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)-
pyridine-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylp-
henyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylp-
yridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclo-
propyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclo-
propyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-
-cyclopropyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-isopr-
opyloxazol-4-yl)pyridine-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-isopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methoxymethyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
dimethylcarbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(hydroxymethyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-m-
ethylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-isopropoxyazetidine-1-carboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate;
2-(1-(((trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5--
methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)ca-
rbonyl)azetidin-3-yl)acetic acid;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-ethoxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-cyanoazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methylazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-ethylazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-isopropoxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(6-methoxy--
5-methylpyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(dimethylamino)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(6-methoxy--
5-methylpyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-methoxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(6-methoxy--
5-methylpyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(2-methoxyethoxy)azetidine-1-carboxylate;
4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((4-(5-methoxy-6-methylpyri-
din-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-cis-3-hydroxyazetidine-1-c-
arboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(hydroxymethyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-ethynylazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate;
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-ethylazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfonyl)methyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-isopropylazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(tert-butyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy--
6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-propoxyazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-propylazetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((dimethylamino)methyl)azetidine-1-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
2-methylmorpholine-4-carboxylate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxy-[1,3'-biazetidine]-1'-carboxylate;
trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfinyl)methyl)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-(methylsulfinyl)azetidine-1-carboxylate;
trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfonyl)methyl)azetidine-1-carboxylate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
trans-4-hydroxycyclohexanecarboxylate;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy)cyclohexanecarboxam-
ide hydrochloride;
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)acetic
acid;
trans-4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-meth-
oxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl dimethylcarbamate;
trans-N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-metho-
xyethoxy)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-metho-
xypropoxy)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-4-(2-Hydroxyethoxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexy-
l)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-4-(3-Hydroxypropoxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohex-
yl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-(dimethylamino)ethoxy)-
-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarbox-
amide; Ethyl
2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-
-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(hydroxymethyl)-N-((t-
rans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-4-(Hydroxymethyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)-
methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(hydroxymethyl)-N-((trans-
-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-4-(Hydroxymethyl)-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-
-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexaneca-
rboxamide;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)-4-(hydroxyme-
thyl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cycloh-
exanecarboxamide;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino-
)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid;
trans-4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-meth-
oxythiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid;
4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythi-
azol-5-yl)phenyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylic acid;
trans-4-(((trans-4-(3-Chloro-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cycl-
opropylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(3-fluoro-1-methy-
l-1H-indazol-5-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4-(4-methoxy-3-methylphen-
yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4-(6-(dimethylamino)pyrid-
in-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((4-(4-methoxy--
3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexanecarbox-
ylic acid;
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-meth-
oxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-me-
thoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxyl-
ic acid;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3--
(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-
-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethyla-
mino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-(((trans-4-(3-Chloro-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cycl-
opropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(3-fluoro-1-m-
ethyl-1H-indazol-5-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3--
methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexanecarboxyl-
ic acid;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-me-
thoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxyl-
ic acid;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-me-
thoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexane-
carboxylic acid;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-meth-
oxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-
-cyclopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid;
2-(trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-m-
ethoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-m-
ethoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4--
(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)ace-
tic acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl-
)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)met-
hyl)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acet-
ic acid;
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3--
(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methy-
lphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethyl-
amino)pyridine-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid;
trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl-
)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid; trans-Methyl
4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphen-
yl)cyclohexyl)methypcarbamoyl)cyclohexanecarboxylate; trans-Methyl
4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythi-
azol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylate; trans-Methyl
4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyrid-
in-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Methyl
4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclo-
propylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylate; Methyl
4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythi-
azol-5-yl)phenyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylate;
trans-4-(Benzyloxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)meth-
yl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-4-((4-meth-
oxybenzyl)oxy)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-Methyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Methyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)p-
yridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
tert-Butyl
(4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylpheny-
l)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)trans-carbamate;
tert-Butyl
(trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate;
trans-Methyl
4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
Ethyl
2-(trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans--
4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)a-
cetate; trans-Methyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methyl-
pyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
Ethyl
2-(trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-met-
hoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate;
Ethyl
2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-
-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetate;
Ethyl
2-(trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)met-
hyl)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acet-
ate; trans-Methyl
4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methy-
lpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Methyl
4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclo-
propyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylate;
2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cy-
clopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-
-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-m-
ethylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((4-(2-Cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-metho-
xy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-
-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylam-
ino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(2-Isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-met-
hylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
trans-2-(4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-
-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)aceti-
c acid;
2-(trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cy-
clopropyl-1H-pyrazol-4-yl)phenyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimeth-
ylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-((4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-met-
hoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
3-(trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)propanoic
acid;
trans-2-(4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-me-
thylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-me-
thylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((cis-4-(5-methoxy-6-meth-
ylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cy-
clopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylami-
no)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methox-
y-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid;
2-(trans-4-((3-(2-Isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-((4-(2-Isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-is-
opropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-is-
opropyloxazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cy-
clopropyloxazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic acid;
2-(trans-4-(((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-
-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl)acetic acid;
trans-Propyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Isopropyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Butyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Pentyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Isobutyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Isopentyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-Propyl
4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate;
trans-N.sup.1-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N.sup.4-(2-hydrox-
yethyl)-N.sup.1-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cycl-
ohexane-1,4-dicarboxamide;
trans-.sup.1-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3--
(2-methoxythiazol-5-yl)phenyl)-N.sup.4-methylcyclohexane-1,4-dicarboxamide-
;
trans-N.sup.1-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(-
3-(2-methoxythiazol-5-yl)phenyl)cyclohexane-1,4-dicarboxamide;
trans-N.sup.1-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-
-(2-methoxythiazol-5-yl)phenyl)-N.sup.4,N.sup.4-dimethylcyclohexane-1,4-di-
carboxamide;
trans-N.sup.1-(2-Hydroxyethyl)-N.sup.4-((trans-4-(4-methoxy-3-methylpheny-
l)cyclohexyl)methyl)-N.sup.4-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexane--
1,4-dicarboxamide;
trans-N.sup.1-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-N.su-
p.1-(2-methoxyethyl)-N.sup.1-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexane--
1,4-dicarboxamide;
trans-N.sup.1-(2-(Dimethylamino)ethyl)-N.sup.4-((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)-N.sup.4-(3-(2-methoxythiazol-5-yl)phenyl)cycl-
ohexane-1,4-dicarboxamide;
trans-N.sup.1(trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-N.sup.-
1-(3-(2-methoxythiazol-5-yl)phenyl)-N.sup.4-(methylsulfonyl)cyclohexane-1,-
4-dicarboxamide; Methyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate;
tert-Butyl
(trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-met-
hoxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl)carbamate; tert-Butyl
((trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-me-
thoxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate;
trans-4-(Aminomethyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)me-
thyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
trans-4-Acetamido-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl-
)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; Methyl
(trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-met-
hoxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl)carbamate;
trans-4-(Acetamidomethyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexy-
l)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;
Methyl
((trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(-
3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate;
trans-N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-me-
thoxythiazol-5-yl)phenyl)-4-(methylsulfonamidomethyl)cyclohexanecarboxamid-
e;
trans-4-Acetamido-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(-
4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(N-methylacetamido)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(methylsulfonamido)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-methoxyacetamido)cyclohexanecarboxamide-
;
2-((trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methypcarbamoyl)cyclohexyl)amino)-2-oxoethyl
acetate;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxyacetam-
ido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexaneca-
rboxamide;
2-((trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methypcarbamoyl)cyclohexyl)amino)-2-oxoe-
thyl methylcarbamate;
trans-4-Butyramido-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-
-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-pentanamidocyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(3-methylbutanamido)cyclohexanecarboxamide-
; Methyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate;
trans-4-Acetamido-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-
-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(methylsulfonamido)cyclohexanecarboxam-
ide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-hydroxyacetami-
do)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecar-
boxamide;
2-((trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4--
(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2--
oxoethyl methylcarbamate; 2-Hydroxyethyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(trans-4-hydroxycyclo-
hexanecarboxamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl-
)cyclohexanecarboxamide;
trans-4-Acetamido-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((4-(4-me-
thoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamid-
e;
2-((4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methyl-
phenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoet-
hyl trans-acetate;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-hydroxyacetamido)--
N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexan-
ecarboxamide;
trans-4-Acetamido-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(-
4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl
acetate;
trans-4-(2-Hydroxyacetamido)-N-(3-(1-isopropyl-1H-pyrazol-4-yl)p-
henyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-
carboxamide;
trans-4-(Acetamidomethyl)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-(-
(trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamid-
e; Methyl
((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-
-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)methyl)carb-
amate;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)-4-(methylsulfonamidomethyl)cyclohe-
xanecarboxamide;
trans-N-(3-(2-Cyclopropyloxazol-4-yl)phenyl)-4-(2-hydroxyacetamido)-N-((t-
rans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
2-((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethy-
l acetate;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)-4-(2-hydroxy-
acetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide;
trans-4-Acetamido-N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-N-((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-4-Acetamido-N-(4-(2-cyclopropyloxazol-4-yl)pyridine-2-yl)-N-((trans-
-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
Methyl
(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5--
methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbam-
ate;
trans-4-(Aminomethyl)-N-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-N--
((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecar-
boxamide;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-acetamidoethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-(methylsulfonamido)ethyl)carbamate;
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methyl
ethane-1,2-diyldicarbamate;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)-N-((trans-4-(5-methoxy-
-6-methylpyridin-2-yl)cyclohexyl)methyl)-4-(methylsulfonamidomethyl)cycloh-
exanecarboxamide; Methyl
((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-
-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)methyl)carbam-
ate; Ethyl
((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4--
(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)met-
hyl)carbamate;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)-4-((2-hydroxyacetamido-
)methyl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyc-
lohexanecarboxamide;
trans-4-Acetamido-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-((t-
rans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
2-((trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxo-
ethyl acetate;
trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-(2-hydroxyaceta-
mido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanec-
arboxamide;
trans-4-Acetamido-N-(4-(Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-
-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
2-((trans
-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl
acetate;
trans-4-(2-Hydroxyacetamido)-N-(4-(Isopropyl-1H-pyrazol-4-yl)pyr-
idin-2-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl-4-(3-methylureido)cyclohexanecarboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl-4-(3-methylureido)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxy-2-methylpropan-
amido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-
carboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxypropanamido)-N--
((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxami-
de;
N-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxetane-3-carboxamid-
e;
trans-4-(2-(1H-Imidazol-1-yl)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl-
)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexa-
necarboxamide;
trans-4-(2-(1H-Imidazol-2-yl)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)p-
henyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-
carboxamide;
N-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)-1-methylazetidine-3-
-carboxamide;
N-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)azetidine-3-carboxamide-
; 2-Hydroxyethyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate;
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetic
acid;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(3-methoxycyclobutanecarboxamido)cyclo-
hexanecarboxamide;
trans-4-(Cyclobutanecarboxamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phen-
yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecar-
boxamide;
trans-4-(cyclobutanecarboxamido)-trans-(4-(2-cyclopropyloxazol-4-
-yl)pyridine-2-yl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-ylcyclohexyl)m-
ethyl)cyclohexanecarboxamide;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)-N-((trans-4-(5-methoxy-
-6-methylpyridin-2-yl)cyclohexyl)methyl)-4-(3-methoxycyclobutanecarboxamid-
o)cyclohexanecarboxamide;
trans-4-(Cyclobutanecarboxamidomethyl)-N-(4-(2-cyclopropyloxazol-4-yl)pyr-
idin-2-yl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)c-
yclohexanecarboxamide;
trans-N-(4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)-4-((3-(dimethylamino)c-
yclobutanecarboxamido)methyl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)-
cyclohexyl)methyl)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfonamido)acetamido)cyclohexan-
ecarboxamide; Methyl
(2-((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl-
)carbamate;
trans-4-(2-Acetamidoacetamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl-
)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarbo-
xamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfonyl)acetamido)cy-
clohexanecarboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfonamido)acetamido)cycloh-
exanecarboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfinyl)acetamido)cyclohexa-
necarboxamide; Methyl
(2-((trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl)car-
bamate;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-(dimethylamino)-
acetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide;
trans-4-(2-Aminoacetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((tr-
ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)acetamido)cyclohexanecarbo-
xamide;
trans-4-(2-Acetamidoacetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phe-
nyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexaneca-
rboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylthio)acetamido)cyclohe-
xanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfinyl)acetamido)cyclohexaneca-
rboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfonyl)acetamido)cyc-
lohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(3-(methylsulfinyl)propanamido)cyclohexane-
carboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(3-(methylsulfonyl)propanamido)cyclohexane-
carboxamide;
trans-4-(2-(1H-Imidazol-4-yl)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)p-
henyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-
carboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)-
acetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(2-hydroxyethoxy)a-
cetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohex-
anecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-(2-hydroxyethoxy)aceta-
mido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanec-
arboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-(3-hydroxypropoxy)acet-
amido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-
carboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-(2-(dimethylamino)etho-
xy)acetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cycl-
ohexanecarboxamide;
trans-4-(2-(2-Aminoethoxy)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phen-
yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecar-
boxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-met-
hoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(2-(methylamino)ethoxy)acetami-
do)cyclohexanecarboxamide;
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2H-tetrazol-5-yl)cyclohexanecarboxamide;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(2H-tetrazol-5-yl)cyclohexanecarboxami-
de;
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol--
3-yl)cyclohexanecarboxamide;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((S)-1-hydroxypropan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((R)-1-hydroxypropan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((R)-2-hydroxypropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((S)-2-hydroxypropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxybutyl)(methyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxy-3-methylbutyl)(methyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((S)-1-hydroxypropan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((R)-1-hydroxypropan-2-yl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((R)-2-hydroxypropyl)carbamate;
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
((S)-2-hydroxypropyl)carbamate; or a pharmaceutically acceptable
salt, or solvate thereof.
46. A pharmaceutical composition comprising a compound of any one
of claims 1-45, or a pharmaceutically acceptable salt, or solvate
thereof, and at least one pharmaceutically acceptable
excipient.
47. The pharmaceutical composition of claim 46, wherein the
pharmaceutical composition is formulated for administration to a
mammal by intravenous administration, subcutaneous administration,
oral administration, inhalation, nasal administration, dermal
administration, or ophthalmic administration.
48. The pharmaceutical composition of claim 46, wherein the
pharmaceutical composition is in the form of a tablet, a pill, a
capsule, a liquid, a suspension, a gel, a dispersion, a solution,
an emulsion, an ointment, or a lotion.
49. A method of treating or preventing a liver disease or condition
in a mammal, comprising administering to the mammal a compound of
any one of claims 1-45, or a pharmaceutically acceptable salt or
solvate thereof.
50. The method of claim 49, wherein the liver disease or condition
is an alcoholic or non-alcoholic liver disease or condition.
51. The method of claim 49, wherein the liver disease or condition
is primary biliary cirrhosis, primary sclerosing cholangitis,
cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic
fatty liver disease (NAFLD).
52. The method of claim 50, wherein the alcoholic liver disease or
condition is fatty liver (steatosis), cirrhosis, or alcoholic
hepatitis.
53. The method of claim 50, wherein the non-alcoholic liver disease
or condition is nonalcoholic steatohepatitis (NASH), or
nonalcoholic fatty liver disease (NAFLD).
54. The method of claim 50, wherein the non-alcoholic liver disease
or condition is nonalcoholic steatohepatitis (NASH).
55. The method of claim 50, wherein the non-alcoholic liver disease
or condition is nonalcoholic steatohepatitis (NASH) and is
accompanied by liver fibrosis.
56. The method of claim 50, wherein the non-alcoholic liver disease
or condition is nonalcoholic steatohepatitis (NASH) without liver
fibrosis.
57. The method of claim 50, wherein the non-alcoholic liver disease
or condition is intrahepatic cholestasis or extrahepatic
cholestasis.
58. A method of treating or preventing a liver fibrosis in a
mammal, comprising administering to the mammal a compound of any
one of claims 1-45, or a pharmaceutically acceptable salt or
solvate thereof.
59. The method of claim 58, wherein the mammal is diagnosed with
hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH),
primary sclerosing cholangitis (PSC), cirrhosis, Wilson's disease,
hepatitis B virus (HBV), HIV associated steatohepatitis and
cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic
steatohepatitis (NASH), primary biliary cirrhosis (PBC), or biliary
cirrhosis.
60. The method of claim 58, wherein the mammal is diagnosed with
nonalcoholic steatohepatitis (NASH).
61. A method of treating or preventing a liver inflammation in a
mammal, comprising administering to the mammal a compound of any
one of claims 1-45, or a pharmaceutically acceptable salt or
solvate thereof.
62. The method of claim 61, wherein the mammal is diagnosed with
hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH),
primary sclerosing cholangitis (PSC), cirrhosis, Wilson's disease,
hepatitis B virus (HBV), HIV associated steatohepatitis and
cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic
steatohepatitis (NASH), primary biliary cirrhosis (PBC), or biliary
cirrhosis.
63. The method of claim 61, wherein the mammal is diagnosed with
nonalcoholic steatohepatitis (NASH).
64. The method of claim 61, wherein the liver inflammation is
associated with inflammation in the gastrointestinal tract.
65. The method of claim 61, wherein the mammal is diagnosed with
inflammatory bowel disease.
66. A method of treating or preventing a gastrointestinal disease
or condition in a mammal, comprising administering to the mammal a
compound of any one of claims 1-45, or a pharmaceutically
acceptable salt or solvate thereof.
67. The method of claim 66, wherein the gastrointestinal disease or
condition is necrotizing enterocolitis, gastritis, ulcerative
colitis, Crohn's disease, inflammatory bowel disease, irritable
bowel syndrome, gastroenteritis, radiation induced enteritis,
pseudomembranous colitis, chemotherapy induced enteritis,
gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer
dyspepsia (NUD), celiac disease, intestinal celiac disease,
post-surgical inflammation, gastric carcinogenesis, graft versus
host disease or any combination thereof.
68. The method of claim 66, wherein the gastrointestinal disease or
condition is irritable bowel syndrome with diarrhea (IBS-D),
irritable bowel syndrome with constipation (IBS-C), mixed IBS
(IBS-M), unsubtyped IBS (IBS-U), or bile acid diarrhea (BAD).
69. A method of treating or preventing a disease or condition in a
mammal that would benefit from treatment with a FXR agonist,
comprising administering to the mammal a compound of any one of
claims 1-45, or a pharmaceutically acceptable salt or solvate
thereof.
70. The method of any one of claims 49-69, further comprising
administering at least one additional therapeutic agent in addition
to the compound of any one of claims 1-45, or a pharmaceutically
acceptable salt or solvate thereof.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/494,272, filed on Sep. 13, 2019, which is a
National Stage Entry of International Application No.
PCT/US2018/022513, filed on Mar. 14, 2018, which claims the benefit
of U.S. Provisional Patent Application No. 62/471,511 filed on Mar.
15, 2017; U.S. Provisional Patent Application No. 62/471,517 filed
on Mar. 15, 2017; U.S. Provisional Patent Application No.
62/471,525 filed on Mar. 15, 2017; U.S. Provisional Patent
Application No. 62/563,488 filed on Sep. 26, 2017; and U.S.
Provisional Patent Application No. 62/563,502 filed on Sep. 26,
2017; each of which are incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] Described herein are compounds that are farnesoid X receptor
agonists, methods of making such compounds, pharmaceutical
compositions and medicaments comprising such compounds, and methods
of using such compounds in the treatment of conditions, diseases,
or disorders associated with farnesoid X receptor activity.
BACKGROUND OF THE INVENTION
[0003] Farnesoid X receptor (FXR) is a nuclear receptor highly
expressed in the liver, intestine, kidney, adrenal glands, and
adipose tissue. FXR regulates a wide variety of target genes
involved in the control of bile acid synthesis and transport, lipid
metabolism, and glucose homeostasis. FXR agonism is a treatment
modality for many metabolic disorders, liver diseases or
conditions, inflammatory conditions, gastrointestinal diseases, or
cell proliferation diseases.
SUMMARY OF THE INVENTION
[0004] In one aspect, described herein are farnesoid X receptor
agonists and uses thereof. In one aspect, described herein is a
compound of Formula (I), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00001##
[0005] wherein, [0006] ring A is a 5-membered heteroaryl that is
thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, oxazolyl,
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, or thiadiazolyl; [0007] or ring A is a 6-membered
heteroaryl that is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
or triazinyl; [0008] or ring A is phenyl; [0009] X.sup.1 is CH or
N; [0010] R.sup.1 is H, D, halogen, --CN, --OH,
--N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, --SH,
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0011] X.sup.2 is CR.sup.2 or N;
[0012] R.sup.2 is H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, --SH,
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0013] or R.sup.1 and R.sup.2 are
taken together with the intervening atoms to form a substituted or
unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2
O or S atoms in the ring; [0014] X.sup.3 is CR.sup.3 or N; [0015]
R.sup.3 is H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; each
X.sup.4 is independently CH or N; [0016] R.sup.4 is H, D, F, or
--CH.sub.3; [0017] R.sup.5 is H, D, F, or --CH.sub.3; [0018] or
R.sup.4 and R.sup.5 are taken together to form a bridge that is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0019] each R.sup.6 is
independently H, D, F, --OH, or --CH.sub.3; [0020] m is 0, 1, or 2;
[0021] R.sup.7 is H, D, halogen, --CN, --OH, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; [0022]
L is absent, --Y.sup.2-L.sup.1-, -L.sup.1-Y.sup.2--,
cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene; [0023]
Y.sup.2 is absent, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.15--, --CH.sub.2--,
--CH.dbd.CH--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)O--, --C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--, or
--NR.sup.15--; [0024] L.sup.1 is absent or substituted or
unsubstituted C.sub.1-C.sub.4alkylene; [0025] R.sup.8 is H, D,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6deuteroalkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, or substituted or unsubstituted monocyclic
heteroaryl; [0026] R.sup.9 is H, D, F or --CH.sub.3; [0027]
R.sup.10 is --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14, --OC(.dbd.O)OR.sup.14,
tetrazolyl, imidazole, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
--S(.dbd.O).sub.2N(R.sup.12).sub.2,
--NR.sup.15S(.dbd.O).sub.2R.sup.14,
--C(.dbd.O)NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2NR.sup.15C(.dbd.O)R.sup.14,
--CH.sub.2N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --C(.dbd.NH)NH.sub.2,
--NHC(.dbd.NH)NH.sub.2, --C(.dbd.O)NHC(.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2OH or --OP(.dbd.O)(OR.sup.15).sub.2; [0028] or
R.sup.10 is -L.sup.2-L.sup.3-L.sup.4-R.sup.13; [0029] L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.6alkylene, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkylene; [0030]
L.sup.3 is absent, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR.sup.15--, --C(.dbd.O)--,
--C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--, --C(.dbd.O)O--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--OP(.dbd.O)(OR.sup.15)O--, or --(OCH.sub.2CH.sub.2).sub.r--, r is
1 or 2; [0031] L.sup.4 is substituted or unsubstituted
C.sub.1-C.sub.6alkylene, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkylene; [0032] R.sup.13 is H, --CN, --OH,
--N(R.sup.12).sub.2, --NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2N(R.sup.12).sub.2, -SR.sup.12,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.14, --SO.sub.3H,
--OP(.dbd.O)(OR.sup.15).sub.2, --C(.dbd.O)R.sup.14,
--OC(.dbd.O)R.sup.14, --CO.sub.2H, --CO.sub.2R.sup.14,
--OC(.dbd.O)OR.sup.14, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, or substituted or unsubstituted monocyclic heteroaryl;
[0033] R.sup.11 is H, D, F, or --CH.sub.3; [0034] or R.sup.9 and
R.sup.11 are taken together to form a bridge that is --CH.sub.2--
or --CH.sub.2CH.sub.2--; [0035] each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; [0036] R.sup.14
is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; [0037] R.sup.15
is H or substituted or unsubstituted C.sub.1-C.sub.6alkyl; [0038]
each R.sup.16 is independently H, D, halogen, --CN, --OH,
--N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted monocyclic C.sub.2-C.sub.6heterocycloalkyl,
substituted or unsubstituted phenyl, or substituted or
unsubstituted monocyclic heteroaryl; [0039] n is 0, 1, or 2.
[0040] Any combination of the groups described above for the
various variables is contemplated herein. Throughout the
specification, groups and substituents thereof are chosen by one
skilled in the field to provide stable moieties and compounds.
[0041] In one aspect, described herein is a pharmaceutical
composition comprising a compound described herein, or a
pharmaceutically acceptable salt, or solvate thereof, and at least
one pharmaceutically acceptable excipient. In some embodiments, the
pharmaceutical composition is formulated for administration to a
mammal by intravenous administration, subcutaneous administration,
oral administration, inhalation, nasal administration, dermal
administration, or ophthalmic administration. In some embodiments,
the pharmaceutical composition is formulated for administration to
a mammal by intravenous administration, subcutaneous
administration, or oral administration. In some embodiments, the
pharmaceutical composition is formulated for administration to a
mammal by oral administration. In some embodiments, the
pharmaceutical composition is in the form of a tablet, a pill, a
capsule, a liquid, a suspension, a gel, a dispersion, a solution,
an emulsion, an ointment, or a lotion. In some embodiments, the
pharmaceutical composition is in the form of a tablet, a pill, or a
capsule.
[0042] In another aspect, described herein is a method of treating
a disease or condition in a mammal that would benefit from FXR
agonism comprising administering a compound as described herein, or
pharmaceutically acceptable salt, or solvate thereof, to the mammal
in need thereof. In some embodiments, the disease or condition is a
metabolic condition. In some embodiments, the disease or condition
is a liver condition.
[0043] In some embodiments, the compound is administered to the
mammal by intravenous administration, subcutaneous administration,
oral administration, inhalation, nasal administration, dermal
administration, or ophthalmic administration.
[0044] In one aspect, described herein is a method of treating or
preventing any one of the diseases or conditions described herein
comprising administering a therapeutically effective amount of a
compound described herein, or a pharmaceutically acceptable salt,
or solvate thereof, to a mammal in need thereof.
[0045] In one aspect, described herein is a method for the
treatment or prevention of a metabolic or liver condition in a
mammal comprising administering a therapeutically effective amount
of a compound described herein, or a pharmaceutically acceptable
salt, or solvate thereof, to the mammal in need thereof. In other
embodiments, the metabolic or liver condition is amenable to
treatment with a FXR agonist. In some embodiments, the method
further comprises administering a second therapeutic agent to the
mammal in addition to the compound described herein, or a
pharmaceutically acceptable salt, or solvate thereof.
[0046] In one aspect, described herein is a method of treating or
preventing a liver disease or condition in a mammal, comprising
administering to the mammal a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof. In some
embodiments, the liver disease or condition is an alcoholic or
non-alcoholic liver disease. In some embodiments, the liver disease
or condition is primary biliary cirrhosis, primary sclerosing
cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or
nonalcoholic fatty liver disease (NAFLD). In some embodiments, the
alcoholic liver disease or condition is fatty liver (steatosis),
cirrhosis, or alcoholic hepatitis. In some embodiments, the
non-alcoholic liver disease or condition is nonalcoholic
steatohepatitis (NASH), or nonalcoholic fatty liver disease
(NAFLD). In some embodiments, the non-alcoholic liver disease or
condition is nonalcoholic steatohepatitis (NASH). In some
embodiments, the non-alcoholic liver disease or condition is
nonalcoholic steatohepatitis (NASH) and is accompanied by liver
fibrosis. In some embodiments, the non-alcoholic liver disease or
condition is nonalcoholic steatohepatitis (NASH) without liver
fibrosis. In some embodiments, the non-alcoholic liver disease or
condition is intrahepatic cholestasis or extrahepatic
cholestasis.
[0047] In one aspect, described herein is a method of treating or
preventing a liver fibrosis in a mammal, comprising administering
to the mammal a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof. In some embodiments, the mammal
is diagnosed with hepatitis C virus (HCV), nonalcoholic
steatohepatitis (NASH), primary sclerosing cholangitis (PSC),
cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV
associated steatohepatitis and cirrhosis, chronic viral hepatitis,
non-alcoholic fatty liver disease (NAFLD), alcoholic
steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), primary
biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments,
the mammal is diagnosed with nonalcoholic steatohepatitis
(NASH).
[0048] In one aspect, described herein is a method of treating or
preventing a liver inflammation in a mammal, comprising
administering to the mammal a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof. In some
embodiments, the mammal is diagnosed with hepatitis C virus (HCV),
nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis
(PSC), cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV
associated steatohepatitis and cirrhosis, chronic viral hepatitis,
non-alcoholic fatty liver disease (NAFLD), alcoholic
steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), primary
biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments,
the mammal is diagnosed with nonalcoholic steatohepatitis (NASH).
In some embodiments, the liver inflammation is associated with
inflammation in the gastrointestinal tract. In some embodiments,
the mammal is diagnosed with inflammatory bowel disease.
[0049] In one aspect, described herein is a method of treating or
preventing a gastrointestinal disease or condition in a mammal,
comprising administering to the mammal a compound of Formula (I),
or a pharmaceutically acceptable salt or solvate thereof. In some
embodiments, the gastrointestinal disease or condition is
necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's
disease, inflammatory bowel disease, irritable bowel syndrome,
gastroenteritis, radiation induced enteritis, pseudomembranous
colitis, chemotherapy induced enteritis, gastro-esophageal reflux
disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac
disease, intestinal celiac disease, post-surgical inflammation,
gastric carcinogenesis, graft versus host disease or any
combination thereof. In some embodiments, the gastrointestinal
disease is irritable bowel syndrome (IBS), irritable bowel syndrome
with diarrhea (IBS-D), irritable bowel syndrome with constipation
(IBS-C), mixed IBS (IBS-M), unsubtyped IBS (IBS-U), or bile acid
diarrhea (BAD)
[0050] In one aspect, described herein is a method of treating or
preventing a disease or condition in a mammal that would benefit
from treatment with a FXR agonist, comprising administering to the
mammal a compound of Formula (I), or a pharmaceutically acceptable
salt or solvate thereof. In some embodiments, the methods described
herein further comprise administering at least one additional
therapeutic agent in addition to the compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof.
[0051] In any of the aforementioned aspects are further embodiments
in which the effective amount of the compound described herein, or
a pharmaceutically acceptable salt thereof, is: (a) systemically
administered to the mammal; and/or (b) administered orally to the
mammal; and/or (c) intravenously administered to the mammal; and/or
(d) administered by inhalation; and/or (e) administered by nasal
administration; or and/or (f) administered by injection to the
mammal; and/or (g) administered topically to the mammal; and/or (h)
administered by ophthalmic administration; and/or (i) administered
rectally to the mammal; and/or (j) administered non-systemically or
locally to the mammal.
[0052] In any of the aforementioned aspects are further embodiments
comprising single administrations of the effective amount of the
compound, including further embodiments in which the compound is
administered once a day to the mammal or the compound is
administered to the mammal multiple times over the span of one day.
In some embodiments, the compound is administered on a continuous
dosing schedule. In some embodiments, the compound is administered
on a continuous daily dosing schedule.
[0053] In any of the aforementioned aspects involving the treatment
of a disease or condition are further embodiments comprising
administering at least one additional agent in addition to the
administration of a compound of Formula (I) described herein, or a
pharmaceutically acceptable salt thereof. In various embodiments,
each agent is administered in any order, including
simultaneously.
[0054] In any of the embodiments disclosed herein, the mammal or
subject is a human.
[0055] In some embodiments, compounds provided herein are
administered to a human.
[0056] In some embodiments, compounds provided herein are orally
administered.
[0057] In some embodiments, described herein is method of treating
or preventing a metabolic disorder in a subject, comprising:
administering to a gastrointestinal tract of the subject a
therapeutically effective amount of one or more of the compounds
described herein, or a pharmaceutically acceptable salt or solvate
thereof, thereby activating farnesoid X receptors (FXR) in the
intestines, and treating or preventing a metabolic disorder in the
subject. In some embodiments, the compound's absorption is
preferentially restricted to within the intestines. In some
embodiments, the method substantially enhances FXR target gene
expression in the intestines while not substantially enhancing FXR
target gene expression in the liver or kidney. In some embodiments,
the method substantially enhances FXR target gene expression in the
intestines while minimizing systemic plasma levels of the delivered
compound. In some embodiments, the method substantially enhances
FXR target gene expression in the intestines and the liver while
minimizing systemic plasma levels of the delivered compound. In
some embodiments, the method substantially enhances FXR target gene
expression in the intestines while not substantially enhancing FXR
target gene expression in the liver or kidney, and while minimizing
systemic plasma levels. In some embodiments, the method
substantially enhances FXR target gene expression in the intestines
and the liver and provides sustained systemic plasma levels of the
delivered compound. In some embodiments, the method reduces or
prevents diet-induced weight gain. In some embodiments, the method
increases a metabolic rate in the subject. In some embodiments, the
increasing the metabolic rate comprises enhancing oxidative
phosphorylation in the subject. In some embodiments, the method
further comprises improving glucose and/or lipid homeostasis in the
subject. In some embodiments, the method results in no substantial
change in food intake and/or fat consumption in the subject. In
some embodiments, the method results in no substantial change in
appetite in the subject. In some embodiments, the metabolic
disorder is selected from obesity, diabetes, insulin resistance,
dyslipidemia or any combination thereof. In some embodiments, the
metabolic disorder is non-insulin dependent diabetes mellitus. In
some embodiments, the method protects against diet-induced weight
gain, reduces inflammation, enhances thermogenesis, enhances
insulin sensitivity in the liver, reduces hepatic steatosis,
promotes activation of BAT, decreases blood glucose, increases
weight loss, or any combination thereof. In some embodiments, the
method enhances insulin sensitivity in the liver and promotes brown
adipose tissue (BAT) activation. In some embodiments, the method
further comprises administering to the subject an insulin
sensitizing drug, an insulin secretagogue, an alpha-glucosidase
inhibitor, a glucagon-like peptide (GLP) agonist, a dipeptidyl
peptidase-4 (DPP-4) inhibitor, nicotinamide ribonucleoside, an
analog of nicotinamide ribonucleoside, or combinations thereof.
[0058] In some embodiments, described herein is a method of
treating or preventing inflammation in an intestinal region of a
subject, comprising: administering to a gastrointestinal tract of
the subject a therapeutically effective amount of one or more of
the compounds described herein, or a pharmaceutically acceptable
salt or solvate thereof, thereby activating FXR receptors in the
intestines, and thereby treating or preventing inflammation in the
intestinal region of the subject. In some embodiments, the
compound's absorption is preferentially restricted to within the
intestines. In some embodiments, the method substantially enhances
FXR target gene expression in the intestines while not
substantially enhancing FXR target gene expression in the liver or
kidney. In some embodiments, the inflammation is associated with a
clinical condition selected from necrotizing enterocolitis,
gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel
disease, irritable bowel syndrome, gastroenteritis, radiation
induced enteritis, pseudomembranous colitis, chemotherapy induced
enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer,
non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac
disease, post-surgical inflammation, gastric carcinogenesis or any
combination thereof. In some embodiments, the one or more FXR
target genes comprises IBABP, OST.alpha., Perl, FGF15, FGF19, SHP
or combinations thereof. In some embodiments, the method further
comprises administering a therapeutically effective amount of an
antibiotic therapy to the subject, wherein the method treats or
prevents inflammation associated with pseudomembranous colitis in
the subject. In some embodiments, the method further comprises
administering to the subject a therapeutically effective amount of
an oral corticosteroid, other anti-inflammatory or immunomodulatory
therapy, nicotinamide ribonucleoside, an analog of nicotinamide
ribonucleoside, or combinations thereof. In some embodiments, the
method increases HSL phosphorylation and .beta.3-adrenergic
receptor expression. In some embodiments, a serum concentration of
the compound in the subject remains below its EC.sub.50 following
administration of the compound.
[0059] In some embodiments, described herein is a method of
treating or preventing a cell proliferation disease in a subject,
comprising administering to a gastrointestinal tract of the subject
a therapeutically effective amount of one or more of the compounds
described herein or a pharmaceutically acceptable salt or solvate
thereof. In some embodiments, the cell proliferation disease is an
adenocarcinoma. In some embodiments, the adenocarcinoma is a colon
cancer. In some embodiments, the treating the adenocarcinoma
reduces the size of the adenocarcinoma, the volume of the
adenocarcinoma, the number of adenocarcinomas, cachexia due to the
adenocarcinoma, delays progression of the adenocarcinoma, increases
survival of the subject, or combinations thereof. In some
embodiments, the method further comprises administering to the
subject an additional therapeutic compound selected from the group
consisting of a chemotherapeutic, a biologic, a radiotherapeutic,
or combinations thereof.
[0060] In some embodiments, described herein is a method of
treating or preventing a liver disease or condition in a subject,
comprising administering to the subject a therapeutically effective
amount of one or more of the compounds described herein, or a
pharmaceutically acceptable salt or solvate thereof. In some
embodiments, the liver disease or condition is an alcoholic or
non-alcoholic liver disease. In some embodiments, the liver disease
or condition is primary biliary cirrhosis, primary sclerosing
cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or
nonalcoholic fatty liver disease (NAFLD). In some embodiments, the
alcoholic liver disease or condition is fatty liver (steatosis),
cirrhosis, or alcoholic hepatitis. In some embodiments, the
non-alcoholic liver disease or condition is nonalcoholic
steatohepatitis (NASH), or nonalcoholic fatty liver disease
(NAFLD). In some embodiments, the non-alcoholic liver disease or
condition is intrahepatic cholestasis or extrahepatic
cholestasis.
[0061] Articles of manufacture, which include packaging material, a
compound described herein, or a pharmaceutically acceptable salt
thereof, within the packaging material, and a label that indicates
that the compound or composition, or pharmaceutically acceptable
salt, pharmaceutically active metabolite, pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate thereof,
is used for the treatment, prevention or amelioration of one or
more symptoms of a disease or condition that would benefit from FXR
agonism, are provided.
[0062] Other objects, features and advantages of the compounds,
methods and compositions described herein will become apparent from
the following detailed description. It should be understood,
however, that the detailed description and the specific examples,
while indicating specific embodiments, are given by way of
illustration only, since various changes and modifications within
the spirit and scope of the instant disclosure will become apparent
to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0063] The nuclear hormone receptor farnesoid X receptor (also
known as FXR or nuclear receptor subfamily 1, group H, member 4
(NR1H4)) (OMIM: 603826) functions as a regulator for bile acid
metabolism. FXR is a ligand-activated transcriptional receptor
expressed in diverse tissues including the adrenal gland, kidney,
stomach, duodenum, jejunum, ileum, colon, gall bladder, liver,
macrophages, and white and brown adipose tissue. FXRs are highly
expressed in tissues that participate in bile acid metabolism such
as the liver, intestines, and kidneys. Bile acids function as
endogenous ligands for FXR such that enteric and systemic release
of bile acids induces FXR-directed changes in gene expression
networks. Bile acids are the primary oxidation product of
cholesterol, and in some cases, upon secretion into the intestines,
are regulators of cholesterol absorption. The rate-limiting step
for conversion of cholesterol into bile acids is catalyzed by
cytochrome p450 enzyme cholesterol 7-.alpha.-hydroxylase (CYP7A1)
and occurs in the liver. The cytochrome p450 enzyme sterol
12-.alpha.-hydroxylase (CYP8B1) mediates production of cholic acid
and determines the relative amounts of the two primary bile acids,
cholic acid and chenodeoxycholic acid. Activation of FXR can
represses the transcription of CYP7A1 and CYP8B1 by increasing the
expression level of the hepatic small heterodimer partner (SHP)
(also known as nuclear receptor subfamily 0, group B, member 2; or
NR0B2) and intestinal expression of fibroblast growth factor 15
(FGF15) in mice and fibroblast growth factor 19 (FGF19) in human.
SHP represses the liver receptor homolog (LRH-1) and hepatocyte
nuclear factor 4alpha (HNFa4), transcription factors that regulate
CYP7A1 and CYP8B1 gene expression. CYP8B1 repression by FXR can be
species-specific and FXR activation may in some cases increase
CYP8B1 expression in humans (Sanyal et al PNAS, 2007, 104, 15665).
In some cases, FGF15/19 released from the intestine then activates
the fibroblast growth factor receptor 4 in the liver, leading to
activation of the mitogen-activated protein kinase (MAPK) signaling
pathway which suppress CYP7A1 and CYP8B1.
[0064] In some embodiments, elevated levels of bile acids have been
associated with insulin resistance. For example, insulin resistance
sometimes leads to a decreased uptake of glucose from the blood and
increased de novo glucose production in the liver. In some
instances, intestinal sequestration of bile acids has been shown to
improve insulin resistance by promoting the secretion of
glucagon-like peptide-1 (GLP1) from intestinal L-cells. GLP-1 is an
incretin derived from the transcription product of the proglucagon
gene. It is released in response to the intake of food and exerts
control in appetite and gastrointestinal function and promotes
insulin secretion from the pancreas. The biologically active forms
of GLP-1 include GLP-1-(7-37) and GLP-1-(7-36)NH.sub.2, which
result from selective cleavage of the proglucagon molecule. In such
cases, activation of FXR leading to decreased production of bile
acids correlates to a decrease in insulin resistance.
[0065] In some embodiments, the activation of FXR also correlates
to the secretion of pancreatic polypeptide-fold such as peptide YY
(PYY or PYY3-36). In some instances, peptide YY is a gut hormone
peptide that modulates neuronal activity within the hypothalamic
and brainstem, regions of the brain involved in reward processing.
In some instances, reduced level of PYY correlates to increased
appetite and weight gain.
[0066] In some instances, the activation of FXR indirectly leads to
a reduction of plasma triglycerides. The clearance of triglycerides
from the bloodstream is due to lipoprotein lipase (LPL). LPL
activity is enhanced by the induction of its activator
apolipoprotein CII, and the repression of its inhibitor
apolipoprotein CIII in the liver occurs upon FXR activation.
[0067] In some cases, the activation of FXR further modulates
energy expenditure such as adipocyte differentiation and function.
Adipose tissue comprises adipocytes or fat cells. In some
instances, adipocytes are further differentiated into brown adipose
tissue (BAT) or white adipose tissue (WAT). The function of BAT is
to generate body heat, while WAT functions as fat storing
tissues.
[0068] In some instances, FXR is widely expressed in the intestine.
In some cases, the activation of FXR has been shown to induce the
expression and secretion of FGF19 (or FGF15 in mouse) in the
intestine. FGF19 is a hormone that regulates bile acid synthesis as
well as exerts an effect on glucose metabolism, lipid metabolism,
and on energy expenditure. In some instances, FGF19 has also been
observed to modulate adipocyte function and differentiation.
Indeed, a study has shown that the administration of FGF19 to
high-fat diet-fed mice increased energy expenditure, modulated
adipocytes differentiation and function, reversed weight gain, and
improved insulin resistance (see, Fu et al., "Fibroblast growth
factor 19 increases metabolic rate and reverses dietary and
leptin-deficient diabetes." Endocrinology 145:2594-2603
(2004)).
[0069] In some cases, intestinal FXR activity has also been shown
to be involved in reducing overgrowth of the microbiome, such as
during feeding (Li et al., Nat Commun 4:2384, 2013). For example, a
study had shown that activation of FXR correlated with increased
expression of several genes in the ileum such as Ang2, iNos, and
Il18, which have established antimicrobial actions (Inagaki et al.,
Proc Natl Acad Sci USA 103:3920-3925, 2006).
[0070] In some cases, FXR has been implicated in barrier function
and immune modulation in the intestine. FXR modulates transcription
of genes involved in bile salt synthesis, transport and metabolism
in the liver and intestine, and in some cases has been shown to
lead to improvements in intestinal inflammation and prevention of
bacterial translocation into the intestinal tract (Gadaleta et al.,
Gut. 2011 April: 60(4): 463-72).
[0071] In some cases, over production of bile acids or improper
transport and re-cycling of bile acids can lead to diarrhea. FXR
modulates transcription of genes involved in bile salt synthesis,
transport and metabolism in the liver and intestine, and in some
cases may lead to improvements in diarrhea Camilleri, Gut Liver.
2015 May; 9(3): 332-339.
[0072] G protein-coupled bile acid receptor 1 (also known as
GPBAR2, GPCR19, membrane-type receptor for bile acids or M-BAR, or
TGRS) is a cell surface receptor for bile acids. Upon activation
with bile acid, TGRS induces the production of intracellular cAMP,
which then triggers an increase in triiodothyronine due to the
activation of deiodinase (DIO2) in BAT, resulting in increased
energy expenditure.
[0073] Hence in some embodiments, regulation of metabolic processes
such as bile acid synthesis, bile-acid circulation, glucose
metabolism, lipid metabolism, or insulin sensitivity is modulated
by the activation of FXR. Furthermore, in some embodiments,
dis-regulation of metabolic processes such as bile acid synthesis,
bile-acid circulation, glucose metabolism, lipid metabolism, or
insulin sensitivity results in metabolic diseases such as diabetes
or diabetes-related conditions or disorders, alcoholic or
non-alcoholic liver disease or condition, intestinal inflammation,
or cell proliferative disorders.
[0074] Disclosed herein, in certain embodiments, are compounds that
have activity as FXR agonists. In some embodiments, the FXR
agonists described herein are structurally distinct from bile
acids, other synthetic FXR ligands, and other natural FXR
ligands.
[0075] In some embodiments, also disclosed herein are methods of
treating or preventing a metabolic disorder, such as diabetes,
obesity, impaired glucose tolerance, dyslipidemia, or insulin
resistance by administering a therapeutically effective amount of
an FXR agonist. In some instances, the compounds are administered
to the GI tract of a subject.
[0076] In additional embodiments, disclosed herein are methods for
treating or preventing alcoholic or non-alcoholic liver disease or
conditions (e.g., cholestasis, primary biliary cirrhosis,
steatosis, cirrhosis, alcoholic hepatitis, non-alcoholic
steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD),
primary sclerosing cholangitis (PSC) or elevated liver enzymes) by
administering a therapeutically effective amount of an FXR agonist
to a subject in need thereof (e.g., via the GI tract). In
additional embodiments, disclosed herein include methods for
treating or preventing cholestasis, cirrhosis, primary biliary
cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic
fatty liver disease (NAFLD), or primary sclerosing cholangitis
(PSC) by administering a therapeutically effective amount of an FXR
agonist to a subject in need thereof. In some embodiments,
disclosed herein include methods for treating or preventing
cholestasis by administering a therapeutically effective amount of
an FXR agonist to a subject in need thereof. In some embodiments,
disclosed herein include methods for treating or preventing primary
biliary cirrhosis by administering a therapeutically effective
amount of an FXR agonist to a subject in need thereof. In some
embodiments, disclosed herein include methods for treating or
preventing NASH by administering a therapeutically effective amount
of an FXR agonist to a subject in need thereof. In some
embodiments, disclosed herein include methods for treating or
preventing NAFLD by administering a therapeutically effective
amount of an FXR agonist to a subject in need thereof.
[0077] In further embodiments, disclosed herein include methods for
treating or preventing inflammation in the intestines and/or a cell
proliferative disorder, such as cancer, by administering a
therapeutically effective amount of an FXR agonist to a subject in
need thereof (e.g., via the GI tract).
[0078] In still further embodiments, disclosed herein include FXR
agonists that modulate one or more of the proteins or genes
associated with a metabolic process such as bile acid synthesis,
glucose metabolism, lipid metabolism, or insulin sensitivity, such
as for example, increase in the activity of FGF19 (FGF15 in mouse),
increase in the secretion of GLP-1, or increase in the secretion of
PYY.
Metabolic Disorders
[0079] Disclosed herein, in certain embodiments, are methods of
treating a metabolic disorder in a subject in need thereof. Also
described herein include methods of preventing a metabolic disorder
in a subject in need thereof. In some instances, these methods
include administering to the subject in need thereof a
therapeutically effective amount of one or more of the compounds
disclosed herein. In some instances, the one or more compounds
disclosed herein are absorbed in the gastrointestinal (GI) tract.
In additional instances, the one or more disclosed compounds
absorbed in the GI tract activates FXR receptors thereby treating
or preventing a metabolic disorder in the subject.
[0080] In some embodiments, the disclosed compounds demonstrate
systemic exposure. In some instances, the disclosed compounds have
local exposure in the intestines, but limited exposure in the liver
or systemically. In some embodiments, local exposure of the
disclosed compounds in the intestines maybe demonstrated by
regulation of FXR target genes in the intestines. In some
embodiments, the target genes may include: SHP, FGF19 (FGF15),
IBABP, C3, OST .alpha./.beta.. In some embodiments, exposure of the
disclosed compounds is about 40%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, 90%, 95%, 99%, 99.5%, or more in the intestines. In some
instances, exposure of the disclosed compounds is about 0.5%, 1%,
5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or less in the systemic
circulation. In some embodiments, the exposure of the FXR agonists
in the intestinal lumen reduces the chance of side effects which
results from systemic action, thereby improving the safety profile
of the therapy. In additional embodiments, the disclosed compounds
enhance FXR target gene expression in the intestines. In additional
embodiments, the disclosed compounds further modulate gene
expressions in the FXR-mediated pathway, such as for example, FGF19
(FGF15) which inhibits CYP7A1 and CYP8B1 gene expression in the
liver. In some instances, the disclosed compounds enhance gene
expression in the FXR-mediated pathway. In other instances, the
disclosed compounds reduce or inhibit gene expression in the
FXR-mediated pathway. In some instances, enhancing is about 1%, 5%,
10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%,
300%, 500%, 1,000%, 5,000%, 10,000%, 50,000%, 100,000%, 500,000%,
or higher in gene expression in the intestines, liver, kidney, or
other tissues relative to the gene expression in the absence of the
disclosed compound. In some cases, reducing is about 100%, 90%,
80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, or less
in gene expression in the intestines, liver, kidney, or other
tissues relative to the gene expression in the absence of the
disclosed compound.
[0081] In some embodiments, the method substantially enhances FXR
target gene expression in the intestines while minimizing systemic
plasma levels of the delivered compound. In some embodiments, the
method substantially enhances FXR target gene expression in the
intestines and the liver while minimizing systemic plasma levels of
the delivered compound. In some embodiments, the method
substantially enhances FXR target gene expression in the intestines
while not substantially enhancing FXR target gene expression in the
liver or kidney, and while minimizing systemic plasma levels. In
some embodiments, the method substantially enhances FXR target gene
expression in the intestines and the liver and provides sustained
systemic plasma levels of the delivered compound.
[0082] In some embodiments, metabolic disorder refers to any
disorder that involves an alteration in the normal metabolism of
carbohydrates, lipids, proteins, nucleic acids or a combination
thereof. In some instances, a metabolic disorder is associated with
either a deficiency or excess in a metabolic pathway resulting in
an imbalance in metabolism of nucleic acids, proteins, lipids,
and/or carbohydrates. Factors affecting metabolism include, but are
not limited to, the endocrine (hormonal) control system (e.g., the
insulin pathway, the enteroendocrine hormones including GLP-1,
oxyntomodulin, PYY or the like), or the neural control system
(e.g., GLP-1 in the brain). Exemplary metabolic disorders include,
but are not limited to, diabetes, insulin resistance, dyslipidemia,
liver disease, inflammation related intestinal conditions, cell
proliferative disorders, or the like.
Diabetes Mellitus and Diabetes-Related Conditions or Disorders
[0083] In some embodiments, disclosed herein are methods of
treating a subject having diabetes mellitus or diabetes-related
condition or disorder with administration of a FXR agonist
described herein. In some instances, diabetes is type II diabetes
or non-insulin-dependent diabetes mellitus (NIDDM). In some
instances, diabetes-related conditions or disorders include
obesity, impaired glucose tolerance, dyslipidemia, and insulin
resistance. In some instances, diabetes-related conditions or
disorders further include secondary complications such as
atherosclerosis, stroke, fatty liver disease, blindness,
gallbladder disease, or polycystic ovary disease. In some cases, a
FXR agonist is administered for the treatment of type II diabetes,
obesity, impaired glucose tolerance, dyslipidemia, insulin
resistance, or secondary complications such as atherosclerosis,
stroke, fatty liver disease, blindness, gallbladder disease, or
polycystic ovary disease.
[0084] In some embodiments, a diabetic subject (e.g., a type II
diabetic subject) is further characterized with a body mass index
(BMI) of 25 or greater, 30 or greater, 35 or greater, 40 or
greater, such as a BMI of 25 to 29, 30 to 34, or 35 to 40.
[0085] In some examples, a FXR agonist described herein reduces or
prevents weight gain in a subject. In some instances, the weight
gain is diet-induced weight gain. In other instances, the weight
gain is non-diet-related, such as familial/genetic obesity or
obesity resulting from medication. In some examples, such methods
reduce or prevent weight gain in the subject by at least 5%, at
least 10%, at least 15%, at least 20%, at least 30%, at least 40%,
at least 50%, or more. In some instances, weight gain is reduced or
prevented by about 5% to about 50%, by about 5% to about 25%, by
about 10% to about 20%, or by about 10% to about 30%. In some
cases, the reduction or prevention of weight gain is relative to
the reduction or prevention of weight gain observed in a subject
not treated with the FXR agonist.
[0086] Similarly, in some cases, the FXR agonist reduces the BMI of
a subject. In some examples, such methods reduce the BMI of a
subject by at least 5%, at least 10%, at least 15%, at least 20%,
at least 25%, at least 30%, or more, relative to a subject not
treated with the FXR agonist. In some instances, the subject is
overweight but not obese. In other instances, the subject is
neither overweight nor obese.
[0087] In some instances, administration of a FXR agonist results
in a decrease in the amount of serum lipids. In some examples, the
decrease in the amount of serum lipids is by at least 5%, at least
10%, at least 15%, at least 20%, at least 30%, at least 50%, at
least 60%, at least 70%, at least 75%, or more. In some cases, the
decrease in the amount of serum lipids is by about 5% to about 50%,
by about 5% to about 25%, by about 10% to about 20%, by about 10%
to about 70%, or by about 10% to about 30%. In some cases, the
decrease in the amount of serum lipids is relative to the amount of
serum lipids observed in a subject not treated with the FXR
agonist.
[0088] In some examples, administration of a FXR agonist results in
a decrease in triglyceride (e.g., hepatic triglyceride) level. In
some instances, the decrease in triglyceride (e.g., hepatic
triglyceride) level is by at least 5%, at least 10%, at least 15%,
at least 20%, at least 30%, at least 50%, at least 60%, at least
70%, at least 75%, or more. In some instances, the decrease in
triglyceride (e.g., hepatic triglyceride) level is by about 5% to
about 50%, by about 5% to about 25%, by about 10% to about 20%, by
about 10% to about 70%, or by about 10% to about 30%. In some
cases, the decrease in triglyceride (e.g., hepatic triglyceride)
level is relative to the triglyceride (e.g., hepatic triglyceride)
level observed in a subject not treated with the FXR agonist.
[0089] In some examples, administration of a FXR agonist results in
an increased insulin sensitivity to insulin in the liver. In some
instances, the increase in insulin sensitivity is by at least 5%,
at least 10%, at least 15%, at least 20%, at least 30%, at least
40%, at least 50%, or more. In some cases, the increase in insulin
sensitivity is by about 5% to about 50%, by about 5% to about 25%,
by about 10% to about 20%, or by about 10% to about 30%. In some
cases, the increase in insulin sensitivity is relative to
sensitivity observed in a subject not treated with the FXR
agonist.
[0090] In some embodiments, administration of a FXR agonist results
in a decrease in the amount of serum insulin in the subject. In
some examples, the decrease in serum insulin is by at least 5%, at
least 10%, at least 15%, at least 20%, at least 30%, at least 50%,
at least 60%, at least 70%, at least 75%, or more. In some
instances, serum insulin is decreased by about 5% to about 50%, by
about 5% to about 25%, by about 10% to about 20%, by about 10% to
about 70%, or by about 10% to about 30%. In some cases, the
decrease in serum insulin level is relative to levels observed in a
subject not treated with the FXR agonist.
[0091] In some embodiments, administration of a FXR agonist results
in a decrease in the amount of serum glucose in the subject. In
some examples, the decrease in serum glucose is by at least 5%, at
least 10%, at least 15%, at least 20%, at least 30%, at least 50%,
at least 60%, at least 70%, at least 75%, or more. In some
instances, serum glucose is decreased by about 5% to about 50%, by
about 5% to about 25%, by about 10% to about 20%, by about 10% to
about 70%, or by about 10% to about 30%. In some cases, the
decrease in serum glucose level is relative to levels observed in a
subject not treated with the FXR agonist.
[0092] In some examples, a FXR agonist described herein increases
browning of white adipose tissue in a subject. In some examples,
the rate of increase of browning of white adipose tissue in the
subject is by at least 5%, at least 10%, at least 15%, at least
20%, at least 30%, at least 40%, at least 50%, or more, relative to
a subject not treated with the FXR agonist.
[0093] In some embodiments, administration of a FXR agonist does
not result in substantial change in food intake and/or fat
consumption in the subject. In some instances, food intake and/or
fat consumption is reduced, such as by less than 15%, less than
10%, or less than 5%. In some embodiments, no substantial change in
appetite in the subject results. In other embodiments, reduction in
appetite is minimal as reported by the subject.
[0094] In some embodiments, administration of a FXR agonist results
in an increase in the metabolic rate in the subject. In some
instances, the FXR agonist increases the metabolic rate in a
subject. In some cases, the metabolic rate in the subject is
increased by at least 5%, at least 10%, at least 15%, at least 20%,
at least 30%, at least 40%, at least 50%, at least 60%, at least
70%, at least 75%, or more. In some instances, the metabolic rate
is increased by about 5% to about 50%, by about 5% to about 25%, by
about 10% to about 20%, by about 10% to about 70%, or by about 10%
to about 30%). In some cases, the increase in metabolic rate is
relative to the rate observed in a subject not treated with the FXR
agonist.
[0095] In some embodiments, the increase in metabolism results from
enhanced oxidative phosphorylation in the subject, which in turn
leads to increased energy expenditure in tissues (such as BAT). In
such instances, the FXR agonist helps to increase the activity of
BAT. In some examples, the activity of BAT is increased by at least
5%, at least 10%, at least 15%, at least 20%, at least 30%, at
least 50%, at least 60%, at least 70%, at least 75%, or more. In
some instances, the activity of BAT is increased by about 5% to
about 50%, by about 5% to about 25%, by about 10% to about 20%, by
about 10% to about 70%, or by about 10% to about 30%. In some
cases, the increase in BAT activity is relative to the activity of
BAT observed in a subject not treated with the FXR agonist.
Alcoholic and Non-Alcoholic Liver Disease or Condition
[0096] Disclosed herein include methods of preventing and/or
treating alcoholic or non-alcoholic liver diseases or conditions.
Exemplary alcoholic or non-alcoholic liver diseases or conditions
include, but are not limited to cholestasis, cirrhosis, steatosis,
alcoholic hepatitis, non-alcoholic steatohepatitis (NASH),
non-alcoholic fatty liver disease (NAFLD), primary sclerosing
cholangitis (PSC), elevated liver enzymes, and elevated
triglyceride levels. In some embodiments, a FXR agonist is used in
the prevention or treatment of alcoholic or non-alcoholic liver
diseases. In some embodiments, a FXR agonist is used in the
prevention or treatment of cholestasis, cirrhosis, steatosis,
alcoholic hepatitis, non-alcoholic steatohepatitis (NASH),
non-alcoholic fatty liver disease (NAFLD), or primary sclerosing
cholangitis (PSC).
Cholestasis
[0097] In some embodiments, a FXR agonist disclosed herein is used
in the treatment of cholestasis in a subject. Cholestasis, an
impairment or cessation in the flow of bile, which in some cases,
causes hepatotoxicity due to the buildup of bile acids and other
toxins in the liver. In some instances, cholestasis is a component
of many liver diseases, including cholelithiasis, cholestasis of
pregnancy, primary biliary cirrhosis (PBC), and primary sclerosing
cholangitis (PSC). In some instances, the obstruction is due to
gallstone, biliary trauma, drugs, one or more additional liver
diseases, or to cancer. In some cases, the enterohepatic
circulation of bile acids enables the absorption of fats and
fat-soluble vitamins from the intestine and allows the elimination
of cholesterol, toxins, and metabolic by-products such as bilirubin
from the liver. In some cases, activation of FXR induces expression
of the canalicular bile transporters BSEP (ABCB11) and multidrug
resistance-related protein 2 (MRP2; ABCC2, cMOAT), and represses
genes involved in bile acid biosynthesis, such as for example
sterol 12a-hydroxylase (CYP8B1) and CYP7A1.
[0098] In some examples, the FXR agonist reduces cholestasis in the
subject by at least 5%, at least 10%, at least 15%, at least 20%,
at least 30%, at least 40%, at least 50%, or more. In some cases,
cholestasis is reduced by about 5% to about 50%, by about 5% to
about 25%, by about 10% to about 20%, or by about 10% to about 30%.
In some instances, the level of cholestasis is relative to the
level of cholestasis in a subject not treated with the FXR
agonist.
Primary Biliary Cirrhosis and Cirrhosis
[0099] In some embodiments, a FXR agonist disclosed herein is used
in the treatment of primary biliary cirrhosis (PBC) in a subject.
PBC is a liver disease that primarily results from autoimmune
destruction of the bile ducts that transport bile acids (BAs) out
of the liver, resulting in cholestasis. As PBC progresses,
persistent toxic buildup of BAs causes progressive liver damage.
Chronic inflammation and fibrosis can advance to cirrhosis. In some
examples, the FXR agonist reduces PBC in the subject by at least
5%, at least 10%, at least 15%, at least 20%, at least 30%, at
least 40%, at least 50%, or more. In some cases, PBC is reduced by
about 5% to about 50%, by about 5% to about 25%, by about 10% to
about 20%, or by about 10% to about 30%. In some instances, the
level of PBC is relative to the level of PBC in a subject not
treated with the FXR agonist.
[0100] In some embodiments, a FXR agonist disclosed herein reduces
cirrhosis in a subject. In some examples, the FXR agonist reduces
cirrhosis in the subject by at least 5%, at least 10%, at least
15%, at least 20%, at least 30%, at least 40%, at least 50%, or
more. In some cases, cirrhosis is reduced by about 5% to about 50%,
by about 5% to about 25%, by about 10% to about 20%, or by about
10% to about 30%. In some instances, the level of cirrhosis is
relative to the level of cirrhosis in a subject not treated with
the FXR agonist.
Non-Alcoholic Fatty Liver Disease and Non-Alcoholic
Steatohepatitis
[0101] Non-alcoholic fatty liver disease (NAFLD) is associated with
excessive fat in the liver (steatosis) and in some cases progresses
to NASH, which is defined by the histologic hallmarks of
inflammation, cell death, and fibrosis. In some instances, primary
NASH is associated with insulin resistance, while secondary NASH is
caused by medical or surgical conditions, or drugs such as, but not
limited to, tamoxifen. In some cases, NASH progresses to advanced
fibrosis, hepatocellular carcinoma, or end-stage liver disease
requiring liver transplantation.
[0102] In some instances, NASH develops as a result of triglyceride
(TGs) imbalance. For example, dysfunctional adipocytes secrete
pro-inflammatory molecules such as cytokines and chemokines leading
to insulin resistance and a failure of lipolysis suppression in the
adipocytes. In some instances, this failure of lipolysis
suppression leads to a release of free fatty acids (FFAs) into the
circulation and uptake within the liver. In some cases, over
accumulation of FFAs in the form of triglycerides (TGs) in lipid
droplets leads to oxidative stress, mitochondrial dysfunction, and
upregulation of pro-inflammatory molecules.
[0103] In some instances, activation of FXR inhibits triglyceride
(TG)/fatty acid (FA) synthesis facilitated by suppressing sterol
regulatory element-binding protein 1c (SREBP1c) via activation of
SHP. In some cases, FXR additionally increases the clearance of TG
by stimulating lipoprotein lipase (LPL) activity as well as the
hepatic uptake of remnants and low-density lipoprotein by inducing
syndecan 1 (SDC1) and the VLDL receptor (VLDLR).
[0104] In some embodiments, a FXR agonist disclosed herein is used
in the treatment of non-alcoholic steatohepatitis (NASH). In some
examples, the FXR agonist reduces NASH the subject by at least 5%,
at least 10%, at least 15%, at least 20%, at least 30%, at least
40%, at least 50%, or more. In some cases, NASH is reduced by about
5% to about 50%, by about 5% to about 25%, by about 10% to about
20%, or by about 10% to about 30%. In some instances, the level of
NASH is relative to the level of NASH in a subject not treated with
the FXR agonist.
[0105] In some embodiments, a FXR agonist disclosed herein is used
in the treatment of NAFLD. In some examples, the FXR agonist
reduces NAFLD in the subject by at least 5%, at least 10%, at least
15%, at least 20%, at least 30%, at least 40%, at least 50%, or
more. In some cases, NAFLD is reduced by about 5% to about 50%, by
about 5% to about 25%, by about 10% to about 20%, or by about 10%
to about 30%. In some instances, the level of NAFLD is relative to
the level of NAFLD in a subject not treated with the FXR agonist.
Steatosis
[0106] In some embodiments, a FXR agonist disclosed herein reduces
fatty liver (steatosis) in a subject. In some examples, the FXR
agonist reduces steatosis in the subject by at least 5%, at least
10%, at least 15%, at least 20%, at least 30%, at least 40%, at
least 50%, or more. In some instances, steatosis is reduced by
about 5% to about 50%, by about 5% to about 25%, by about 10% to
about 20%, or by about 10% to about 30%. In some instances, the
level of steatosis is relative to the level of steatosis in a
subject not treated with the FXR agonist. Ballooning
[0107] Hepatocyte ballooning, a feature denoting cellular injury,
is a feature of NASH. Ballooning is a feature that denotes
progressive NAFL (types 3 and 4). The term applies to enlarged,
swollen-appearing hepatocytes; the affected cells are often
intermixed in areas of steatosis and, in classic steatohepatitis,
in the perivenular regions. Hepatocellular ballooning is most
commonly noted in regions of H & E-detectable perisinusoidal
fibrosis. Ballooned hepatocytes are most easily noted when they
contain MH (either typical or poorly formed). Hepatocyte ballooning
is a structural manifestation of microtubular disruption and severe
cell injury.
[0108] In some embodiments, a FXR agonist disclosed herein reduces
liver ballooning in a subject. In some examples, the FXR agonist
reduces liver ballooning in the subject by at least 5%, at least
10%, at least 15%, at least 20%, at least 30%, at least 40%, at
least 50%, or more. In some instances, liver ballooning is reduced
by about 5% to about 50%, by about 5% to about 25%, by about 10% to
about 20%, or by about 10% to about 30%. In some instances, the
liver ballooning is relative to the level of liver ballooning in a
subject not treated with the FXR agonist.
Alcoholic Hepatitis
[0109] In some embodiments, a FXR agonist disclosed herein reduces
alcoholic hepatitis in a subject. In some examples, the FXR agonist
reduces alcoholic hepatitis in the subject by at least 5%, at least
10%, at least 15%, at least 20%, at least 30%, at least 40%, at
least 50%, or more. In some instances, the level of alcoholic
hepatitis is reduced by about 5% to about 50%, by about 5% to about
25%, by about 10% to about 20%, or by about 10% to about 30%. In
some instances, the level of alcoholic hepatitis is relative to the
level of alcoholic hepatitis in a subject not treated with the FXR
agonist.
Primary Sclerosing Cholangitis
[0110] In some embodiments, a FXR agonist disclosed herein is used
in the treatment of primary sclerosing cholangitis (PSC). PSC is a
chronic and progressive cholestatic liver disease. PSC is
characterized by progressive inflammation, fibrosis, and stricture
formation in liver ducts. Common symptoms include pruritus and
jaundice. The disease is strongly associated with inflammatory
bowel disease (IBD)--about 5% of patients with ulcerative colitis
will have PSC. Up to 70% of patients with PSC also have IBD, most
commonly ulcerative colitis.
Additional Alcoholic and Non Alcoholic Liver Diseases or
Conditions
[0111] In some embodiments, a FXR agonist disclosed herein reduces
liver enzymes in a subject. In some examples, the FXR agonist
reduce liver enzymes (e.g., serum ALT and/or AST levels) in the
subject by at least 5%, at least 10%, at least 15%, at least 20%,
at least 30%, at least 40%, at least 50%, or more. In some
instances, the level of liver enzymes is reduced by about 5% to
about 50%, by about 5% to about 25%, by about 10% to about 20%, or
by about 10% to about 30%. In some instances, the level of liver
enzymes is relative to the level of liver enzymes in a subject not
treated with the FXR agonist.
[0112] In some embodiments, a FXR agonist disclosed herein reduces
liver triglycerides in a subject. In some examples, the FXR agonist
reduces liver triglycerides in the subject by at least 5%, at least
10%, at least 15%, at least 20%, at least 30%, at least 40%, at
least 50%, or more. In some instances, the level of liver
triglycerides is reduced by about 5% to about 50%, by about 5% to
about 25%, by about 10% to about 20%, or by about 10% to about 30%.
In some instances, the level of liver triglycerides is relative to
the level of liver triglycerides in a subject not treated with the
FXR agonist.
Inflammatory Intestinal Condition
[0113] Disclosed herein are methods of treating or preventing an
inflammatory intestinal condition. Exemplary inflammatory
conditions include necrotizing enterocolitis (NEC), gastritis,
ulcerative colitis, inflammatory bowel disease, irritable bowel
syndrome, pseudomembranous colitis, gastroenteritis, radiation
induced enteritis, chemotherapy induced enteritis,
gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer
dyspepsia (NUD), celiac disease, intestinal celiac disease,
gastrointestinal complications following bariatric surgery, gastric
carcinogenesis, or gastric carcinogenesis following gastric or
bowel resection. In some embodiments, the inflammatory condition is
NEC and the subject is a newborn or prematurely born infant. In
some embodiments, the subject is enterally-fed infant or
formula-fed infant.
[0114] In some embodiments, a FXR agonist disclosed herein is
administered to a subject having an inflammatory intestinal
condition. In some embodiments, a FXR agonist disclosed herein is
administered to a subject having necrotizing enterocolitis (NEC),
gastritis, ulcerative colitis, inflammatory bowel disease,
irritable bowel syndrome, pseudomembranous colitis,
gastroenteritis, radiation induced enteritis, chemotherapy induced
enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer,
non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac
disease, gastrointestinal complications following bariatric
surgery, gastric carcinogenesis, or gastric carcinogenesis
following gastric or bowel resection.
[0115] In some embodiments, a FXR agonist disclosed herein reduces
inflammation of the intestines in a subject (such as a human). In
some examples, the FXR agonist reduces intestinal inflammation in
the subject by at least 5%, at least 10%, at least 15%, at least
20%, at least 30%, at least 40%, at least 50%, or more. In some
instances, intestinal inflammation is reduced by about 5% to about
50%, by about 5% to about 25%, by about 10% to about 20%, or by
about 10% to about 30%. In some instances, the level of intestinal
inflammation is relative to the level of intestinal inflammation in
a subject not treated with the FXR agonist.
Gastrointestinal Diseases
[0116] Disclosed herein, in certain embodiments, are methods of
treating or preventing a gastrointestinal disease in a subject in
need thereof, comprising administering to the subject a farnesoid X
receptor (FXR) agonist as described herein. In some embodiments,
the gastrointestinal disease is irritable bowel syndrome (IBS),
irritable bowel syndrome with diarrhea (IBS-D), irritable bowel
syndrome with constipation (IBS-C), mixed IBS (IBS-M), unsubtyped
IBS (IBS-U), or bile acid diarrhea (BAD).
Irritable Bowel Syndrome
[0117] Irritable bowel syndrome (IBS) is a combination of symptoms
including abdominal pain and changes in bowel movement patterns
that persists over an extended period of time, often years. The
causes of IBS remain unclear; however, gut motility problems, food
sensitivity, genetic factors, small intestinal bacterial
overgrowth, and gut-brain axis problems are thought to have a
potential role. In some instances, IBS is accompanied with diarrhea
and is categorized as IBS with diarrhea (IBS-D). In some instances,
IBS is accompanied with constipation and is categorized as IBS with
constipation (IBS-C). In some instances, IBS is accompanied with an
alternating pattern of diarrhea and constipation and is categorized
as mixed IBS (IBS-M). In some instances, IBS is not accompanied
with either diarrhea or constipation and is categorized as
unsubtyped IBS (IBS-U). In some instances, IBS has four different
variations: IBS-D, IBS-C, IBS-M, and IBS-U.
[0118] In some embodiments, the symptoms of IBS are mimicked by a
different condition. In some embodiments, sugar maldigestion,
celiac disease, gluten intolerance without celiac disease,
pancreatic exocrine insufficiency, small bowel bacterial
overgrowth, microscopic colitis, or bile acid malabsorption (BAM)
mimic IBS-D. In some embodiments, anismus, pelvic floor dyssynergia
or puborectalis spasm, or descending perineum syndrome mimic
IBS-C.
[0119] In some embodiments, an FXR agonist disclosed herein is used
in the treatment of IBS or any of its variations in a mammal. In
some examples, an FXR agonist therapeutic agent reduce IBS symptoms
in the mammal by at least 5%, at least 10%, at least 15%, at least
20%, at least 30%, at least 40%, at least 50%, or more.
Bile Acid Malabsorption
[0120] Bile acid malabsorption (BAM), also known as bile acid
diarrhea (BAD), bile acid-induced diarrhea, cholerheic or
choleretic enteropathy, or bile salt malabsorption, is a condition
in which the presence of bile acids in the colon causes diarrhea.
BAM is caused by a number of conditions such as Crohn's disease,
cholecystectomy, coeliac disease, radiotherapy, and pancreatic
diseases. In some instances, BAM is caused by medications such as
metformin. In some embodiments, BAM is caused by an overproduction
of bile acids. Bile acid synthesis is negatively regulated by the
ileal hormone fibroblast growth factor 19 (FGF-19); low levels of
FGF-19 lead to an increase in bile acids. FXR activation promotes
the synthesis of FGF-19, consequently lowering the levels of bile
acids.
[0121] In some embodiments, an FXR agonist disclosed herein is used
in the treatment of BAM in a mammal. In some embodiments, an FXR
agonist disclosed herein decreases bile acid synthesis. In some
embodiments, an FXR agonist disclosed herein decreases bile acid
levels. In some embodiments, an FXR agonist and an additional
therapeutic agent disclosed herein prevent BAD. In some examples,
an FXR agonist reduces BAM symptoms in the mammal by at least 5%,
at least 10%, at least 15%, at least 20%, at least 30%, at least
40%, at least 50%, or more.
Graft vs. Host Disease (GvHD)
[0122] Graft vs. host disease (GvHD) is a medical complication that
arises after a transplant of tissue or cells from a
histo-incompatible donor (i.e. a genetically or immunologically
different donor). Immune cells in the donated tissue or cells
(graft) recognize the recipient (the host) as foreign and initiate
and attack. Non-limiting examples of transplanted tissue or cells
that give rise to GvHD are blood products, stem cells such as bone
marrow cells, and organs. There are different types of GvHD
depending on where the symptoms manifest or develop: skin GvHD,
liver GvHD, eye GvHD, neuromuscular GvHD, genitourinary tract GvHD,
and gastrointestinal (GI) tract GvHD. Symptoms of GI tract GvHD
include difficulty swallowing, pain with swallowing, weight loss,
nausea, vomiting, diarrhea, and/or abdominal cramping. GI tract
GvHD results in sloughing of the mucosal membrane and severe
intestinal inflammation. Inflammation of the biliary epithelium is
amenable to be controlled by nuclear receptors such as the
glucocorticoid receptor (GR), FXR, or the peroxisome
proliferator-activated receptors (PPARs).
[0123] In some embodiments, an FXR agonist disclosed herein is used
in the treatment of GvHD or a complication of GvHD in a mammal. In
some embodiments, an FXR agonist disclosed herein is used in the
treatment of GI tract GvHD or a complication of GI tract GvHD in a
mammal. In some examples, an FXR agonist reduces GI tract GvHD or a
complication of GI tract GvHD in the mammal by at least 5%, at
least 10%, at least 15%, at least 20%, at least 30%, at least 40%,
at least 50%, or more. In some cases, GI tract GvHD or a
complication of GI tract GvHD is reduced by about 5% to about 50%,
by about 5% to about 25%, by about 10% to about 20%, or by about
10% to about 30%. In some embodiments, an FXR agonist disclosed
herein decreases intestinal inflammation caused by GI tract GvHD.
In some embodiments, an FXR agonist disclosed herein reduces
intestinal inflammation caused by GI tract GvHD reduced by about 5%
to about 50%, by about 5% to about 25%, by about 10% to about 20%,
or by about 10% to about 30%.
Kidney Diseases
[0124] Disclosed herein, in certain embodiments, are methods of
treating or preventing a kidney disease in a subject in need
thereof, comprising administering to the subject a farnesoid X
receptor (FXR) agonist described herein. In some embodiments, the
kidney disease is associated with a liver disease. In some
embodiments, the kidney disease is associated with a fibrotic liver
disease. In some embodiments, the kidney disease is associated with
a metabolic liver disease. In some embodiments, the kidney disease
is associated with a metabolic condition such as but not limited to
diabetes, metabolic syndrome, NAFLD, insulin resistance, fatty acid
metabolism disorder, and cholestasis. In some embodiments, the
kidney disease is diabetic nephropathy, kidney disease associated
with fibrosis, kidney disease not associated with fibrosis, renal
fibrosis, or any combination thereof.
Diabetic Nephropathy
[0125] Diabetic nephropathy is a kidney disease characterized by
damage to the kidney's glomeruli. Diabetes contributes to an
excessive production of reactive oxygen species, which leads to
nephrotic syndrome and scarring of the glomeruli. As diabetic
nephropathy progresses, the glomerular filtration barrier (GFB) is
increasingly damaged and consequently, proteins in the blood leak
through the barrier and accumulate in the Bowman's space.
[0126] In some embodiments, an FXR agonist disclosed herein is used
in the treatment of diabetic nephropathy in a mammal.
Renal Fibrosis
[0127] Renal fibrosis is characterized by activation of fibroblasts
and excessive deposition of extracellular matrix or connective
tissue in the kidney, which is a hallmark of chronic kidney
disease. FXR plays an important role in protecting against renal
fibrosis. Activation of FXR suppresses renal fibrosis and decreases
accumulation of extracellular matrix proteins in the kidney.
[0128] In some embodiments, an FXR agonist disclosed herein is used
in the treatment of renal fibrosis in a mammal.
[0129] In one aspect, described herein is a method of treating or
preventing a kidney disease or condition in a mammal, comprising
administering to the mammal an FXR agonist disclosed herein, or a
pharmaceutically acceptable salt or solvate thereof. In some
embodiments, the kidney disease or condition is diabetic
nephropathy, kidney disease associated with fibrosis, kidney
disease not associated with fibrosis, renal fibrosis, kidney
disease associated with a metabolic disease, chronic kidney
disease, polycystic kidney disease, acute kidney disease, or any
combination thereof.
Cell Proliferation Disease
[0130] Further disclosed herein are methods of preventing or
treating cell proliferation diseases, for example, in certain types
of cancer. In some embodiments, the FXR agonists disclosed herein
are used in the prevention or treatment of adenocarcinomas, or a
carcinoma derived from glandular tissue or in which the tumor cells
form recognizable glandular structures. In some embodiments,
adenocarcinomas are classified according to the predominant pattern
of cell arrangement, as papillary, alveolar, or according to a
particular product of the cells, as mucinous adenocarcinoma. In
some instances, adenocarcinomas are observed for example, in colon,
kidney, breast, cervix, esophagus, gastric, pancreas, prostate, or
lung.
[0131] In some embodiments, the compounds disclosed herein are used
in the prevention or treatment of a cancer of the intestine, such
as colon cancer, e.g. cancer that forms in the tissues of the colon
(the longest part of the large intestine), or a cancer of another
part of the intestine, such as the jejunum, and/or ileum. In some
instances, colon cancer is also referred to as "colorectal cancer."
In some instances, the most common type of colon cancer is colon
adenocarcinoma.
[0132] In some cases, cancer progression is characterized by
stages, or the extent of cancer in the body. Staging is usually
based on the size of the tumor, the presence of cancer in the lymph
nodes, and the presence of the cancer in a site other than the
primary cancer site. Stages of colon cancer include stage I, stage
II, stage III and stage IV. In some embodiments, colon
adenocarcinoma is from any stage. In other embodiments, colon
adenocarcinoma is a stage I cancer, a stage II cancer or a stage
III cancer.
[0133] In some embodiments, a FXR agonist described herein is
administered to a subject having a stage I, stage II, stage III, or
stage IV cancer. In some instances, a FXR agonist described herein
is administered to a subject having a stage I, stage II, or stage
III colon adenocarcinoma.
[0134] In some embodiments, a FXR agonist disclosed herein further
reduces the tumor burden in a subject. In some examples, the FXR
agonist reduces tumor burden (such as colon tumor burden) in the
subject by at least 5%, at least 10%, at least 15%, at least 20%,
at least 30%, at least 40%, at least 50%, or more. In some
instances, tumor burden is reduced by about 5% to about 50%, by
about 5% to about 25%, by about 10% to about 20%, or by about 10%
to about 30%. In some instances, the level of tumor burden is
relative to the level of tumor burden in a subject not treated with
the FXR agonist.
[0135] In some instances, a FXR agonist disclosed herein further
reduces tumor size and/or volume in a subject. In some cases, the
FXR agonist reduces tumor size and/or volume (such as a colon
tumor) in the subject by at least 5%, at least 10%, at least 15%,
at least 20%, at least 30%, at least 40%, at least 50%, or more. In
some instances, tumor size is reduced by about 5% to about 50%, by
about 5% to about 25%, by about 10% to about 20%, or by about 10%
to about 30%. In some instances, the tumor size is relative to the
tumor size in a subject not treated with the FXR agonist.
[0136] In additional embodiments, a FXR agonist disclosed herein
reduces effects of cachexia due to a tumor in a subject. In some
examples, the FXR agonist reduce the effect of cachexia (such as
due to a colon tumor) in the subject by at least 5%, at least 10%,
at least 15%, at least 20%, at least 30%, at least 40%, at least
50%, or more. In some instances, the effect of cachexia is reduced
by about 5% to about 50%, by about 5% to about 25%, by about 10% to
about 20%, or by about 10% to about 30%. In some instances, the
effect of cachexia is relative to the effect of cachexia in a
subject not treated with the FXR agonist.
[0137] In other embodiments, a FXR agonist disclosed herein
increases survival rates of a subject with a tumor. In some cases,
the FXR agonist increases the survival rate of a subject with a
tumor (such as a colon cancer) in the subject by at least 5%, at
least 10%, at least 15%, at least 20%, at least 30%, at least 40%,
at least 50%, or more. In some instances, survival rate is
increased by about 5% to about 50%, by about 5% to about 25%, by
about 10% to about 20%, or by about 10% to about 30%. In some
instances, the survival rate is relative to the survival rate in a
subject not treated with the FXR agonist.
Compounds
[0138] Compounds described herein, including pharmaceutically
acceptable salts, prodrugs, active metabolites and pharmaceutically
acceptable solvates thereof, are farnesoid X receptor agonists.
[0139] In one aspect, described herein is a compound of Formula
(I), or a pharmaceutically acceptable salt, or solvate thereof:
##STR00002##
[0140] wherein, [0141] ring A is a 5-membered heteroaryl that is
thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, oxazolyl,
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, or thiadiazolyl; [0142] or ring A is a 6-membered
heteroaryl that is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
or triazinyl; [0143] or ring A is phenyl; [0144] X.sup.1 is CH or
N; [0145] R.sup.1 is H, D, halogen, --CN, --OH,
--N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, --SH,
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0146] X.sup.2 is CR.sup.2 or N;
[0147] R.sup.2 is H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, --SH,
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0148] or R.sup.1 and R.sup.2 are
taken together with the intervening atoms to form a substituted or
unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2
O or S atoms in the ring; [0149] X.sup.3 is CR.sup.3 or N; [0150]
R.sup.3 is H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; [0151]
each X.sup.4 is independently CH or N; [0152] R.sup.4 is H, D, F,
or --CH.sub.3; [0153] R.sup.5 is H, D, F, or --CH.sub.3; [0154] or
R.sup.4 and R.sup.5 are taken together to form a bridge that is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0155] each R.sup.6 is
independently H, D, F, --OH, or --CH.sub.3; [0156] m is 0, 1, or 2;
[0157] R.sup.7 is H, D, halogen, --CN, --OH, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; [0158]
L is absent, --Y.sup.2-L.sup.1-, -L.sup.1-Y.sup.2--,
cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene; [0159]
Y.sup.2 is absent, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.15--, --CH.sub.2--,
--CH.dbd.CH--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)O--, --C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--, or
--NR.sup.15--; [0160] L.sup.1 is absent or substituted or
unsubstituted C.sub.1-C.sub.4alkylene; [0161] R.sup.8 is H, D,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6deuteroalkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, or substituted or unsubstituted monocyclic
heteroaryl; [0162] R.sup.9 is H, D, F or --CH.sub.3; [0163]
R.sup.10 is --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14, --OC(.dbd.O)OR.sup.14,
tetrazolyl, imidazole, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
--S(.dbd.O).sub.2N(R.sup.12).sub.2,
--NR.sup.15S(.dbd.O).sub.2R.sup.14,
--C(.dbd.O)NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2NR.sup.15C(.dbd.O)R.sup.14,
--CH.sub.2N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --C(.dbd.NH)NH.sub.2,
--NHC(.dbd.NH)NH.sub.2, --C(.dbd.O)NHC(.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2OH or --OP(.dbd.O)(OR.sup.15).sub.2; [0164] or
R.sup.10 is -L.sup.2-L.sup.3-L.sup.4-R.sup.13; [0165] L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.6alkylene, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkylene; [0166]
L.sup.3 is absent, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR'.sup.s-, --C(.dbd.O)--,
--C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--, --C(.dbd.O)O--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--OP(.dbd.O)(OR.sup.15)O--, or --(OCH.sub.2CH.sub.2).sub.r--, r is
1 or 2; [0167] L.sup.4 is substituted or unsubstituted
C.sub.1-C.sub.6alkylene, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkylene; [0168] R.sup.13 is H, --CN, --OH,
--N(R.sup.12).sub.2, --NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2N(R.sup.12).sub.2, --SR.sup.12,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.14, --SO.sub.3H,
--OP(.dbd.O)(OR.sup.15).sub.2, --C(.dbd.O)R.sup.14,
--OC(.dbd.O)R.sup.14, --CO.sub.2H, --CO.sub.2R.sup.14,
--OC(.dbd.O)OR.sup.14, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, or substituted or unsubstituted monocyclic heteroaryl;
[0169] R.sup.11 is H, D, F, or --CH.sub.3; [0170] or R.sup.9 and
R.sup.11 are taken together to form a bridge that is --CH.sub.2--
or --CH.sub.2CH.sub.2--; [0171] each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; [0172] R.sup.14
is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; [0173] R.sup.15
is H or substituted or unsubstituted C.sub.1-C.sub.6alkyl; [0174]
each R.sup.16 is independently H, D, halogen, --CN, --OH,
--N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O)(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted monocyclic C.sub.2-C.sub.6heterocycloalkyl,
substituted or unsubstituted phenyl, or substituted or
unsubstituted monocyclic heteroaryl; [0175] n is 0, 1, or 2.
[0176] In another aspect, described herein is a compound of Formula
(I), or a pharmaceutically acceptable salt, or solvate thereof:
##STR00003##
[0177] wherein, [0178] ring A is a 5-membered heteroaryl that is
furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, triazolyl,
tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl;
[0179] or ring A is a 6-membered heteroaryl that is pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; [0180] or ring A
is phenyl; [0181] X.sup.1 is CH or N; [0182] R.sup.1 is H, D,
halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0183] X.sup.2 is CR.sup.2 or N;
[0184] R.sup.2 is H, D, halogen, --CN, --OH, --N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.15).sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; [0185]
or R.sup.1 and R.sup.2 are taken together with the intervening
atoms to form a substituted or unsubstituted fused 5-membered ring
with 0-3 N atoms and 0-2 O or S atoms in the ring; [0186] X.sup.3
is CR.sup.3 or N; [0187] R.sup.3 is H, D, halogen, --CN, --OH,
--N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl), C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; [0188]
each X.sup.4 is independently CH or N; [0189] R.sup.4 is H, D, F,
or --CH.sub.3; [0190] R.sup.5 is H, D, F, or --CH.sub.3; [0191] or
R.sup.4 and R.sup.5 are taken together to form a bridge that is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0192] each R.sup.6 is
independently H, D, F, --OH, or --CH.sub.3; [0193] m is 0, 1, or 2;
[0194] R.sup.7 is H, D, halogen, --CN, --OH, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, or C.sub.1-C.sub.4heteroalkyl; [0195]
L is absent, --Y.sup.2-L.sup.1-, -L.sup.1-Y.sup.2--,
cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene; [0196]
Y.sup.2 is absent, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.15--, --CH.sub.2--,
--CH.dbd.CH--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)O--, --C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--, or
--NR.sup.15--; [0197] L.sup.1 is absent or substituted or
unsubstituted C.sub.1-C.sub.4alkylene; [0198] R.sup.8 is H, D,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6deuteroalkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl,
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--CO.sub.2(C.sub.1-C.sub.4alkyl), --C(.dbd.O)N(R.sup.15).sub.2,
--S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(R.sup.15).sub.2, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, or substituted or unsubstituted monocyclic
heteroaryl; [0199] R.sup.9 is H, D, F or --CH.sub.3; [0200] Y is
--CR10R.sup.11--; [0201] R.sup.10 is --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14,
--OC(.dbd.O)OR.sup.14, tetrazolyl, imidazole,
--S(.dbd.O).sub.2N(R.sup.12).sub.2,
--NR.sup.15S(.dbd.O).sub.2R.sup.14,
--C(.dbd.O)NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2NR.sup.15C(.dbd.O)R.sup.14,
--CH.sub.2N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --C(.dbd.NH)NH.sub.2,
--NHC(.dbd.NH)NH.sub.2, --C(.dbd.O)NHC(.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2OH or --OP(.dbd.O)(OR.sup.15).sub.2; [0202] or
R.sup.10 is -L.sup.2-L.sup.3-L.sup.4-R.sup.13; [0203] L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.6alkylene, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkylene; [0204]
L.sup.3 is absent, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR.sup.15--, --C(.dbd.O)--,
--C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--, --C(.dbd.O)O--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.15--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--OP(.dbd.O)(OR.sup.15)O--, or --(OCH.sub.2CH.sub.2).sub.r--, r is
1 or 2; [0205] L.sup.4 is substituted or unsubstituted
C.sub.1-C.sub.6alkylene, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkylene; [0206] R.sup.13 is H, --CN, --OH,
--N(R.sup.12).sub.2, --NR.sup.15S(.dbd.O).sub.2R.sup.14,
--S(.dbd.O).sub.2N(R.sup.12).sub.2, --SR.sup.12,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.14, --SO.sub.3H,
--OP(.dbd.O)(OR.sup.15).sub.2, --C(.dbd.O)R.sup.14,
--OC(.dbd.O)R.sup.14, --CO.sub.2H, --CO.sub.2R.sup.14,
--OC(.dbd.O)OR.sup.14, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, or substituted or unsubstituted monocyclic heteroaryl;
[0207] R.sup.11 is D, or --CH.sub.3; [0208] or R.sup.9 and R.sup.11
are taken together to form a bridge that is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0209] each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1--C.sub.4heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; [0210] R.sup.14
is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl; [0211] R.sup.15
is H or substituted or unsubstituted C.sub.1-C.sub.6alkyl; [0212]
each R.sup.16 is independently H, D, halogen, --CN, --OH,
--N(R.sup.15).sub.2,
--NR.sup.15S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--S(C.sub.1-C.sub.4alkyl), --S(.dbd.O).sub.2(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)(C.sub.1-C.sub.4alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.4alkyl),
--NR.sup.15C(.dbd.O)(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)N(R.sup.15).sub.2,
--NR.sup.15C(.dbd.O)O(C.sub.1-C.sub.4alkyl),
--OC(.dbd.O)N(R.sup.15).sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4deuteroalkoxy, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4fluoroalkoxy, C.sub.1-C.sub.4heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted monocyclic C.sub.2-C.sub.6heterocycloalkyl,
substituted or unsubstituted phenyl, or substituted or
unsubstituted monocyclic heteroaryl; [0213] n is 0, 1, or 2.
[0214] For any and all of the embodiments, substituents are
selected from among a subset of the listed alternatives. For
example, in some embodiments m is 0, 1, or 2. In some embodiments,
m is 0 or 1. In some embodiments, m is 0. In some embodiments, n is
0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments,
n is 0.
[0215] In some embodiments, ring A is a 5-membered heteroaryl that
is thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl. In some
embodiments, ring A is thiazolyl. In some embodiments, ring A is
oxazolyl. In some embodiments, ring A is a 5-membered heteroaryl
that is pyrazolyl, pyrrolyl, or oxadiazolyl. In some embodiments,
ring A is pyrazolyl. In some embodiments, ring A is a 5-membered
heteroaryl that is imidazolyl, triazolyl, tetrazolyl, or
thiadiazolyl.
[0216] In some embodiments,
##STR00004## ##STR00005##
[0217] In some embodiments,
##STR00006## ##STR00007##
[0218] In some embodiments,
##STR00008## ##STR00009##
[0219] In some embodiments,
##STR00010##
In some embodiments,
##STR00011##
In some embodiments,
##STR00012##
In some embodiments,
##STR00013##
In some embodiments,
##STR00014##
[0220] In some embodiments,
##STR00015##
In some embodiments,
##STR00016##
In some embodiments,
##STR00017##
In some embodiments,
##STR00018##
In some embodiments,
##STR00019##
[0221] In some embodiments,
##STR00020##
In some embodiments
##STR00021##
[0222] In some embodiments,
##STR00022##
In some embodiments,
##STR00023##
[0223] In some embodiments,
##STR00024##
[0224] In some embodiments,
##STR00025##
[0225] In some embodiments, Y is --CR.sup.10R.sup.11--.
[0226] In some embodiments, L is absent, --O--, --S--,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2O--, --OCH.sub.2--,
--CH.sub.2NR.sup.15--, --NR.sup.15CH.sub.2--, --CH.dbd.CH--,
--C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--, --OC(.dbd.O)O--,
--C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--,
--NR.sup.15--, cyclopropylene, cyclobutylene or
bicyclo[1.1.1]pentylene.
[0227] In some embodiments, L is absent, --O--, --S--,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2O--, --OCH.sub.2--,
--CH.sub.2NR.sup.15--, --NR.sup.15CH.sub.2--, --CH.dbd.CH--,
--C(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)--,
--OC(.dbd.O)NR.sup.15--, --NR.sup.15C(.dbd.O)O--,
--NR.sup.15C(.dbd.O)NR.sup.15--, --NR.sup.15S(.dbd.O).sub.2--,
--NR.sup.15--, cyclopropylene, cyclobutylene or
bicyclo[1.1.1]pentylene. In some embodiments, L is absent or
--C.ident.C--. In some embodiments, L is absent. In some
embodiments, L is --C.ident.C--.
[0228] In some embodiments, R.sup.9 is H; R.sup.11 is H; or R.sup.9
and R.sup.11 are taken together to form a bridge that is
--CH.sub.2CH.sub.2--.
[0229] In some embodiments, the compound of Formula (I) has the
structure of Formula (II), or a pharmaceutically acceptable salt or
solvate thereof:
##STR00026##
[0230] In some embodiments, R.sup.4 is H; R.sup.5 is H; or R.sup.4
and R.sup.5 are taken together to form a bridge that is
--CH.sub.2CH.sub.2--.
[0231] In some embodiments, L is absent.
[0232] In some embodiments, the compound of Formula (I) has the
structure of Formula (III), or a pharmaceutically acceptable salt
or solvate thereof:
##STR00027##
[0233] In some embodiments, the compound of Formula (I) has the
structure of Formula (IV), or a pharmaceutically acceptable salt or
solvate thereof:
##STR00028##
[0234] In some embodiments, the compound of Formula (I) has the
structure of Formula (V), or a pharmaceutically acceptable salt or
solvate thereof:
##STR00029##
[0235] In some embodiments, the compound of Formula (I) has the
structure of Formula (VII), or a pharmaceutically acceptable salt
or solvate thereof:
##STR00030##
[0236] In some embodiments, the compound of Formula (I) has the
structure of Formula (VIII), or a pharmaceutically acceptable salt
or solvate thereof:
##STR00031##
[0237] In some embodiments, R.sup.1.degree. is --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14,
--OC(.dbd.O)OR.sup.14, --NR.sup.15S(.dbd.O).sub.2R.sup.14,
--CH.sub.2N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)R.sup.14,
--C(.dbd.O)N(R.sup.12).sub.2, --NR.sup.15C(.dbd.O)OR.sup.14,
--OC(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --S(.dbd.O).sub.2OH or
--OP(.dbd.O)(OR.sup.15).sub.2; or R.sup.10 is
-L.sup.2-L.sup.3-L.sup.4-R'.sup.3; L.sup.2 is absent, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2--,
or --CH.sub.2NHCH.sub.2-; L.sup.3 is absent, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --C(.dbd.O)--,
--C(.dbd.O)NH--, --NHC(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)O--, --OC(.dbd.O)NH--, --NHC(.dbd.O)NH--,
--NHC(.dbd.O)O--, --OP(.dbd.O)(OR.sup.15)O--, or
--(OCH.sub.2CH.sub.2).sub.r--, r is 1 or 2; L.sup.4 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH.sub.2CH(OH)--, --CH(CH.sub.2OH)--, --CH(CH.sub.2OH)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(OH)CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH.sub.2OCH.sub.2--,
--CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2OCH.sub.2--,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2SCH.sub.2--,
--CH.sub.2SCH.sub.2CH.sub.2--, --CH.sub.2--NHCH.sub.2-- or
--CH.sub.2NHCH.sub.2CH.sub.2--.
[0238] In some embodiments, R.sup.10 is --CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14, --OC(.dbd.O)OR.sup.14,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, --OC(.dbd.O)N(R.sup.12).sub.2, or
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2; or R.sup.10 is
-L.sup.2-L.sup.3-L.sup.4-R.sup.13; L.sup.2 is absent, or
--CH.sub.2--; L.sup.3 is absent, --O--, --NH--, --C(.dbd.O)NH--,
--NHC(.dbd.O)--, --OC(.dbd.O)NH--, or --NHC(.dbd.O)O--; L.sup.4 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.2OH)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or --CH.sub.2CH(OH)CH.sub.2--.
[0239] In some embodiments, R.sup.14 is C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4heteroalkyl, monosubstituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, monosubstituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, monosubstituted or unsubstituted
phenyl, monosubstituted or unsubstituted benzyl, or monosubstituted
or unsubstituted monocyclic heteroaryl.
[0240] In some embodiments, R.sup.14 is C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4deuteroalkyl, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4heteroalkyl, substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted cyclopentyl, substituted or unsubstituted
cyclohexyl, substituted or unsubstituted aziridinyl, substituted or
unsubstituted azetidinyl, substituted or unsubstituted
pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted
or unsubstituted oxetanyl, substituted or unsubstituted
tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl,
substituted or unsubstituted tetrahydrothiopyranyl, substituted or
unsubstituted morpholinyl, substituted or unsubstituted
thiomorpholinyl, or substituted or unsubstituted piperazinyl,
substituted or unsubstituted phenyl, substituted or unsubstituted
benzyl, or substituted or unsubstituted monocyclic heteroaryl.
[0241] In some embodiments, R.sup.10 is --CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14, --OC(.dbd.O)OR.sup.14,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, --OC(.dbd.O)N(R.sup.12).sub.2, or
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2; or R.sup.10 is
-L.sup.2-L.sup.3-L.sup.4-R.sup.13; L.sup.2 is absent, or
--CH.sub.2--; L.sup.3 is absent, --O--, --NH--, --C(.dbd.O)NH--,
--NHC(.dbd.O)--, --OC(.dbd.O)NH--, or --NHC(.dbd.O)O--; L.sup.4 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.2OH)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or --CH.sub.2CH(OH)CH.sub.2--;
R.sup.14 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted cyclobutyl, substituted or unsubstituted
cyclopentyl, substituted or unsubstituted cyclohexyl, substituted
or unsubstituted azetidinyl, substituted or unsubstituted
pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted
or unsubstituted oxetanyl, substituted or unsubstituted
tetrahydropyranyl, substituted or unsubstituted
tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, or
substituted or unsubstituted piperazinyl.
[0242] In some embodiments, R.sup.14 is C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4deuteroalkyl, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4heteroalkyl, substituted or unsubstituted
cyclobutyl, substituted or unsubstituted cyclopentyl, substituted
or unsubstituted cyclohexyl, substituted or unsubstituted
azetidinyl, substituted or unsubstituted pyrrolidinyl, or
substituted or unsubstituted piperidinyl.
[0243] In some embodiments, R.sup.13 is H, --CN, --OH,
--N(R.sup.12).sub.2, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).sub.2, --CO.sub.2H, --C(.dbd.O)NHCH.sub.3,
--OC(.dbd.O)NHCH.sub.3, NHC(.dbd.O)CH.sub.3, NHC(.dbd.O)OCH.sub.3,
NHS(.dbd.O).sub.2CH.sub.3, SO.sub.2CH.sub.3, substituted or
unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl,
substituted or unsubstituted cyclopentyl, substituted or
unsubstituted cyclohexyl, substituted or unsubstituted phenyl, or
substituted or unsubstituted monocyclic heteroaryl.
[0244] In some embodiments, R.sup.10 is --CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, or
--OC(.dbd.O)N(R.sup.12).sub.2.
[0245] In some embodiments, R.sup.10 is --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.14, --OC(.dbd.O)R.sup.14,
--NR.sup.15S(.dbd.O).sub.2R.sup.14, --CH.sub.2N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, --OC(.dbd.O)N(R'.sup.2).sub.2,
--NR.sup.15C(.dbd.O)N(R.sup.12).sub.2, --S(.dbd.O).sub.2OH or
--OP(.dbd.O)(OR.sup.15).sub.2; or R.sup.10 is
-L.sup.2-L.sup.3-L.sup.4-R'.sup.3; L.sup.2 is absent, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2--,
or --CH.sub.2NHCH.sub.2--; L.sup.3 is absent, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --C(.dbd.O)--,
--C(.dbd.O)NH--, --NHC(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--OC(.dbd.O)NH--, --NHC(.dbd.O)NH--, --NHC(.dbd.O)O--,
--OP(.dbd.O)(OR.sup.15)O--, or --(OCH.sub.2CH.sub.2).sub.r--, r is
1 or 2; L.sup.4 is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--,
--CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2OCH.sub.2--,
--CH.sub.2SCH.sub.2--, --CH.sub.2SCH.sub.2CH.sub.2--,
--CH.sub.2NHCH.sub.2-- or --CH.sub.2NHCH.sub.2CH.sub.2--.
[0246] In some embodiments, R.sup.10 is --CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, or --OC(.dbd.O)N(R.sup.12).sub.2; or
R.sup.10 is -L.sup.2-L.sup.3-L.sup.4-R'.sup.3; L.sup.2 is absent,
or --CH.sub.2--; L.sup.3 is absent, --O--, --NH--, --C(.dbd.O)NH--,
--NHC(.dbd.O)--, --OC(.dbd.O)NH--, or --NHC(.dbd.O)O--; L.sup.4 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--.
[0247] In some embodiments, R.sup.13 is H, --CN, --OH,
--N(R.sup.12).sub.2, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).sub.2, substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted cyclopentyl, substituted or unsubstituted
cyclohexyl, substituted or unsubstituted phenyl, or substituted or
unsubstituted monocyclic heteroaryl.
[0248] In some embodiments, R.sup.10 is --CH.sub.2OH,
C.sub.1-C.sub.6heteroalkyl, --CO.sub.2H,
--NR.sup.15C(.dbd.O)R.sup.14, --C(.dbd.O)N(R.sup.12).sub.2,
--NR.sup.15C(.dbd.O)OR.sup.14, or
--OC(.dbd.O)N(R.sup.12).sub.2.
[0249] In some embodiments, no more than two X.sup.2, X.sup.3,
X.sup.4, X.sup.4 are N.
[0250] In some embodiments, if both X.sup.4 are N then X.sup.2 is
CR.sup.2 and X.sup.3 is CR.sup.3; or if one X.sup.4 is N and the
other X.sup.4 is CH then only one of X.sup.2 and X.sup.3 is N.
[0251] In some embodiments, the 6-membered ring containing X.sup.2,
X.sup.3, X.sup.4, X.sup.4 has no more than two N atoms in the
ring.
[0252] In some embodiments, X.sup.2 is CR.sup.2; X.sup.3 is
CR.sup.3 or N; each X.sup.4 is CH; or each X.sup.4 is N; or one
X.sup.4 is N and the other X.sup.4 is CH.
[0253] In some embodiments, X.sup.2 is CR.sup.2; X.sup.3 is
CR.sup.3; each X.sup.4 is CH; or each X.sup.4 is N; or one X.sup.4
is N and the other X.sup.4 is CH.
[0254] In some embodiments, X.sup.2 is CR.sup.2; X.sup.3 is
CR.sup.3; each X.sup.4 is CH.
[0255] In some embodiments, X.sup.2 is CR.sup.2; X.sup.3 is
CR.sup.3; each X.sup.4 is N; or one X.sup.4 is N and the other
X.sup.4 is CH.
[0256] In some embodiments, X.sup.2 is CR.sup.2; X.sup.3 is N; each
X.sup.4 is CH; or each X.sup.4 is N; or one X.sup.4 is N and the
other X.sup.4 is CH.
[0257] In some embodiments, R.sup.1 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --SCH(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O)CH.sub.2CH.sub.3, --S(.dbd.O)CH(CH.sub.3).sub.2,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2CH.sub.3,
--S(.dbd.O).sub.2CH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2; R.sup.2 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)(CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --SCH(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O)CH.sub.2CH.sub.3, --S(.dbd.O)CH(CH.sub.3).sub.2,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2CH.sub.3,
--S(.dbd.O).sub.2CH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2; or R.sup.1 and R.sup.2 are taken
together with the intervening atoms to form a substituted or
unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2
O or S atom in the ring that is a substituted or unsubstituted
dihydrofuranyl, substituted or unsubstituted dioxolyl, substituted
or unsubstituted furanyl, substituted or unsubstituted thienyl,
substituted or unsubstituted pyrrolyl, substituted or unsubstituted
oxazolyl, substituted or unsubstituted thiazolyl, substituted or
unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl,
substituted or unsubstituted triazolyl, substituted or
unsubstituted isoxazolyl, substituted or unsubstituted
isothiazolyl, substituted or unsubstituted dihydropyrrolyl,
substituted or unsubstituted pyridinyl, substituted or
unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl,
substituted or unsubstituted pyridazinyl, or substituted or
unsubstituted dioxinyl; R.sup.3 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)(CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, or --CH.sub.2N(CH.sub.3).sub.2.
[0258] In some embodiments, R.sup.1 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, or --CH.sub.2N(CH.sub.3).sub.2; R.sup.2 is H,
D, F, Cl, --CN, --OH, --NH.sub.2, --NH(CH.sub.3),
--N(CH.sub.3).sub.2, --NHS(.dbd.O).sub.2CH.sub.3,
--OC(.dbd.O)(CH.sub.3).sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3,
--NHC(.dbd.O)CH.sub.3, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2; or R.sup.1 and R.sup.2 are taken
together with the intervening atoms to form a substituted or
unsubstituted fused 5-membered ring with 0-3 N atoms and 0-2 O or S
atom in the ring that is a substituted or unsubstituted
dihydrofuranyl, substituted or unsubstituted dioxolyl, substituted
or unsubstituted furanyl, substituted or unsubstituted thienyl,
substituted or unsubstituted pyrrolyl, substituted or unsubstituted
oxazolyl, substituted or unsubstituted thiazolyl, substituted or
unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl,
substituted or unsubstituted triazolyl, substituted or
unsubstituted isoxazolyl or substituted or unsubstituted
isothiazolyl; R.sup.3 is H, D, F, Cl, --CN, --OH, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --NHS(.dbd.O).sub.2CH.sub.3,
--OC(.dbd.O)(CH.sub.3, --CO.sub.2H, --CO.sub.2CH.sub.3,
--NHC(.dbd.O)CH.sub.3, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, --CD.sub.3, --OCD.sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2.
[0259] In some embodiments, R.sup.1 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --SCH.sub.3,
--CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or
--OCH.sub.2CF.sub.3; R.sup.2 is H, D, F, Cl, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --SCH.sub.3,
--CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or --OCH.sub.2CF.sub.3;
R.sup.3 is H, D, F, Cl, --CH.sub.3, --OCH.sub.3, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, or --OCF.sub.3.
[0260] In some embodiments, R.sup.1 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or
--OCH.sub.2CF.sub.3; R.sup.2 is H, D, F, Cl, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, or --OCH.sub.2CF.sub.3; R.sup.3 is H, D,
F, Cl, --CH.sub.3, --OCH.sub.3, --CD.sub.3, --OCD.sub.3,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, or --OCF.sub.3.
[0261] In some embodiments, R.sup.1 is --OH, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, --OCH.sub.3,
--SCH.sub.3, --CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or
--OCH.sub.2CF.sub.3; R.sup.2 is H, D, F, Cl, --CH.sub.3,
--CD.sub.3, --CH.sub.2F, --CHF.sub.2, or --CF.sub.3; R.sup.3 is
H.
[0262] In some embodiments, R.sup.1 is --OH, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, --OCH.sub.3,
--CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or --OCH.sub.2CF.sub.3;
R.sup.2 is H, D, F, Cl, --CH.sub.3, --CD.sub.3, --CH.sub.2F,
--CHF.sub.2, or --CF.sub.3; R.sup.3 is H.
[0263] In some embodiments,
##STR00032##
[0264] In some embodiments,
##STR00033##
[0265] In some embodiments,
##STR00034##
[0266] In some embodiments,
##STR00035##
In some embodiments,
##STR00036##
In some embodiments,
##STR00037##
[0267] In some embodiments, X.sup.2 is N; X.sup.3 is N; each
X.sup.4 is CH.
[0268] In some embodiments,
##STR00038##
[0269] In some embodiments, the compound has the following
structure of Formula (IX), or a pharmaceutically acceptable salt or
solvate thereof:
##STR00039##
[0270] In some embodiments, R.sup.1 is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --OC(.dbd.O)CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, or --CH.sub.2N(CH.sub.3).sub.2.
[0271] In some embodiments, IV is H, D, F, Cl, --CN, --OH,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or
--OCH.sub.2CF.sub.3.
[0272] In some embodiments, R.sup.1 is --OH, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, --OCH.sub.3,
--CD.sub.3, --OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, or
--OCH.sub.2CF.sub.3.
[0273] In some embodiments, R.sup.8 is H, D, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CHFCH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NHCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2CH.sub.3, --C(.dbd.O)CH(CH.sub.3).sub.2,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH(CH.sub.3).sub.2, --C(.dbd.O)NHCH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2NHCH.sub.3, substituted
or unsubstituted cyclopropyl, substituted or unsubstituted
cyclobutyl, substituted or unsubstituted cyclopentyl, substituted
or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl,
substituted or unsubstituted tetrahydrofuranyl, substituted or
unsubstituted tetrahydropyranyl, or substituted or unsubstituted
tetrahydrothiopyranyl.
[0274] In some embodiments, R.sup.8 is H, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --CD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CHFCH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NHCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted cyclopentyl, substituted or unsubstituted
cyclohexyl, substituted or unsubstituted oxetanyl, substituted or
unsubstituted tetrahydrofuranyl, or substituted or unsubstituted
tetrahydropyranyl.
[0275] In some embodiments, R.sup.8 is H, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or
tetrahydropyranyl.
[0276] In some embodiments, each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4deuteroalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, substituted
or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl. In some
embodiments, each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4heteroalkyl, substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl,
substituted or unsubstituted monocyclic heteroaryl. In some
embodiments, each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4heteroalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl, or
substituted or unsubstituted monocyclic heteroaryl. In some
embodiments, each R.sup.12 is independently H,
C.sub.1-C.sub.4alkyl, or substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl. In some embodiments, each R.sup.12
is independently H or C.sub.1-C.sub.4alkyl.
[0277] In some embodiments, when two R.sup.12 are attached to an N
atom, one R.sup.12 is independently H or C.sub.1-C.sub.4alkyl, and
the other R.sup.12 is H, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4deuteroalkyl, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted benzyl, substituted or
unsubstituted monocyclic heteroaryl.
[0278] In some embodiments, when two R.sup.12 are attached to an N
atom, one R.sup.12 is independently H or C.sub.1-C.sub.4alkyl, and
the other R.sup.12 is H, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted benzyl, substituted or
unsubstituted monocyclic heteroaryl. In some embodiments, when two
R.sup.12 are attached to an N atom, one R.sup.12 is H or
C.sub.1-C.sub.4alkyl, and the other R.sup.12 is H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4heteroalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted benzyl,
substituted or unsubstituted monocyclic heteroaryl. In some
embodiments, when two R.sup.12 are attached to an N atom, one
R.sup.12 is independently H or C.sub.1-C.sub.4alkyl, and the other
R.sup.12 is H, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4heteroalkyl,
substituted or unsubstituted C.sub.2-C.sub.6heterocycloalkyl, or
substituted or unsubstituted monocyclic heteroaryl. In some
embodiments, when two R.sup.12 are attached to an N atom, one
R.sup.12 is independently H or C.sub.1-C.sub.4alkyl, and the other
R.sup.12 is H, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4heteroalkyl, or
substituted or unsubstituted C.sub.2-C.sub.6heterocycloalkyl.
[0279] In some embodiments, R.sup.14 is C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4deuteroalkyl, C.sub.1-C.sub.4fluoroalkyl,
C.sub.1-C.sub.4heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted benzyl, or substituted or
unsubstituted monocyclic heteroaryl.
[0280] In some embodiments, R.sup.14 is C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted benzyl, or substituted or
unsubstituted monocyclic heteroaryl. In some embodiments, R.sup.14
is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4heteroalkyl, substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or
unsubstituted phenyl, or substituted or unsubstituted monocyclic
heteroaryl. In some embodiments, R.sup.14 is
C.sub.1-C.sub.4alkyl.
[0281] In some embodiments, each R.sup.16 is independently is H, D,
F, Cl, --CN, --OH, --NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.3,
--C(.dbd.O)CH.sub.3, --OC(.dbd.O)CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3, --C.ident.CH,
--C.ident.CCH.sub.3, --C.ident.CCH.sub.2CH.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2, substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted cyclopentyl, substituted or unsubstituted
cyclohexyl, substituted or unsubstituted aziridinyl, substituted or
unsubstituted azetidinyl, substituted or unsubstituted
pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted
or unsubstituted tetrahydrofuranyl, substituted or unsubstituted
tetrahydropyranyl, substituted or unsubstituted
tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl,
substituted or unsubstituted thiomorpholinyl, or substituted or
unsubstituted piperazinyl.
[0282] In some embodiments, each R.sup.16 is independently is H, D,
F, Cl, --CN, --OH, --NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--NHS(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.3,
--C(.dbd.O)CH.sub.3, --OC(.dbd.O)CH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --NHC(.dbd.O)CH.sub.3, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3, --C.ident.CH,
--C.ident.CCH.sub.3, --C.ident.CCH.sub.2--CH.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --CD.sub.3,
--OCD.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3, or
--CH.sub.2N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,
morpholinyl, thiomorpholinyl, or piperazinyl.
[0283] In some embodiments, each R.sup.16 is independently is H, D,
F, Cl, --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, --SCH.sub.3, --SCH.sub.2CH.sub.3,
--SCH(CH.sub.3).sub.2, --CD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, substituted or unsubstituted
cyclopropyl, or substituted or unsubstituted cyclobutyl. In some
embodiments, each R.sup.16 is independently is H, D, F, Cl,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, --CD.sub.3, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, substituted or unsubstituted
cyclopropyl, or substituted or unsubstituted cyclobutyl. In some
embodiments, each R.sup.16 is independently is H, D, F, Cl,
--CH.sub.3, --CH.sub.2CH.sub.3, --CD.sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, or --CH.sub.2CF.sub.3.
[0284] In some embodiments, the compound has the following
structure of Formula (X), or a pharmaceutically acceptable salt or
solvate thereof:
##STR00040##
[0285] In some embodiments, the compound has the following
structure of Formula (XI) or
[0286] Formula (XII), or a pharmaceutically acceptable salt or
solvate thereof:
##STR00041##
[0287] Any combination of the groups described above for the
various variables is contemplated herein. Throughout the
specification, groups and substituents thereof are chosen by one
skilled in the field to provide stable moieties and compounds.
[0288] In some embodiments, compounds described herein include, but
are not limited to, those described in Table 1 and Table 2.
TABLE-US-00001 TABLE 1 Com- pound No Structure Chemical Name 1
##STR00042## trans-4-((3-(2-cyclopropylthiazol-5-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 1.01 ##STR00043##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 1.02 ##STR00044##
4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)
((4-(6-(dimethylamino)pyridin-3-yl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl trans-
methylcarbamate 1.03 ##STR00045##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(3-fluoro-1-methyl- 1H-indazol-5-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl methylcarbamate 1.04 ##STR00046##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 1.05 ##STR00047##
4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- methylcarbamate 1.06 ##STR00048##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl carbamate 1.07 ##STR00049##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl) cyclohexyl methyl carbonate 1.08 ##STR00050##
4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans-carbamate 1.09 ##STR00051##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(3-fluoro-1-methyl-
1H-indazol-5-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 1.10 ##STR00052##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 2 ##STR00053##
trans-4-((3-(3-cyclopropylisothiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 2.01 ##STR00054##
trans-4-(((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)(3-
(2-methoxythiazol-5- yl)phenyl)carbamoyl)cyclohexyl methylcarbamate
2.02 ##STR00055## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 2.03 ##STR00056## 4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexyl trans- methylcarbamate 2.04
##STR00057## trans-4-(((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)(3-
(thiazol-2-ylethynyl)phenyl)carbamoyl) cyclohexyl methylcarbamate
2.05 ##STR00058## 4-(((4-(4-Methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)(3-(thiazol-2-ylethynyl) phenyl)carbamoyl)cyclohexyl
trans- methylcarbamate 2.06 ##STR00059##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 2.07 ##STR00060##
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)
((4-(4-methoxy-3-methylphenyl)bicyclo
[2.2.2]octan-1-yl)methyl)carbamoyl) cyclohexyl
trans-methylcarbamate 2.08 ##STR00061##
4-((3-(3-Cyclopropylisothiazol-5-yl)
phenyl)((4-(4-methoxy-3-methylphenyl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl trans-
methylcarbamate 3 ##STR00062##
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)
((4-(6-(dimethylamino)pyridin-3-yl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl trans-
methylcarbamate 3.01 ##STR00063##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl ethylcarbamate 3.02 ##STR00064##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin--yl)cyclohexyl)methyl) 2carbamoyl)cyclohexyl
methylcarbamate 3.03 ##STR00065##
4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((4-(6-(dimethylamino)pyridin-
3-yl)bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl trans-
methylcarbamate 3.04 ##STR00066##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 3.05 ##STR00067## trans-4-((3-(2-Cyopropyloxazol-4-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridine-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 4 ##STR00068##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-hydroxyethyl) carbamate 4.01 ##STR00069##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl(2-hydroxyethyl) carbamate 4.02 ##STR00070##
4-((3-(2-Cyclopropylthiazol-5-yl)
phenyl)((4-(4-methoxy-3-methylphenyl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl (2-
hydroxyethyl)trans-carbamate 4.03 ##STR00071##
4-((3-(2-Cyclopropylthiazol-5-yl)
phenyl)((4-(6-(dimethylamino)pyridin-
3-yl)bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl (2-
hydroxyethyl)trans-carbamate 4.04 ##STR00072##
4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
(2- hydroxyethyl)trans-carbamate 4.05 ##STR00073##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl isopropylcarbamate 4.06 ##STR00074##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- methoxyazetidine-1-carboxylate 4.07
##STR00075## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl morpholine-4- carboxylate 4.08 ##STR00076##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl cyclopropylcarbamate 4.09 ##STR00077##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2- (dimethylamino)ethyl)carbamate 4.10
##STR00078## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (3- hydroxypropyl)carbamate 4.11 ##STR00079##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (3- (dimethylamino)propyl)carbamate 4.12
##STR00080## 4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((4-(6-(dimethylamino)
pyridin-3-yl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
(2- hydroxyethyl)trans-carbamate 4.13 ##STR00081##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl ((1H-imidazol-2- yl)methyl)carbamate 4.14
##STR00082## tert-Butyl (2-((((trans-4-((3-(1-
cyclopropyl-1H-pyrazol-4-yl)phenyl)
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)oxy)carbonyl)amino)ethyl) (methyl)carbamate 4.15
##STR00083## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl ((1H-imidazol-4- yl)methyl)carbamate 4.16
##STR00084## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-aminoethyl) carbamate 4.17 ##STR00085##
tert-Butyl 3-((((trans-4-((3-(1-
cyclopropyl-1H-pyrazol-4-yl)phenyl)
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)oxy)carbonyl)amino) azetidine-1-carboxylate 4.18
##STR00086## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl azetidin-3- ylcarbamate 4.19 ##STR00087##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl) carbamate 4.20 ##STR00088##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (4- (dimethylamino)butyl)carbamate 4.21
##STR00089## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (5- (dimethylamino)pentyl)carbamate 4.22
##STR00090## trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridine-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate 4.23 ##STR00091##
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)
((4-(6-(dimethylamino)pyridin-3-yl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl trans-(2-
hydroxyethyl)carbamate 4.24 ##STR00092##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl) carbamate 4.25 ##STR00093##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- hydroxyazetidine-1-carboxylate 4.26
##STR00094## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 4.27 ##STR00095##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 4.28 ##STR00096##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-((methylthio) methyl)azetidine-1-carboxylate
5 ##STR00097## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
ethylcarbamate 5.01 ##STR00098##
trans-4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.02 ##STR00099##
trans-4-((4-(2-Isopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.03 ##STR00100##
trans-4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.04 ##STR00101##
trans-4-((4-(2-Isopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.05 ##STR00102## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropylthiazol-5-yl)pyridin-2- yl)carbamoyl)cyclohexyl
methylcarbamate 5.06 ##STR00103## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(3-(2-cyclopropylthiazol-5-yl)phenyl) carbamoyl)cyclohexyl
methylcarbamate 5.07 ##STR00104## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(2-cyclopropylthiazol-5-yl)pyridin-2- yl)carbamoyl)cyclohexyl
methylcarbamate 5.08 ##STR00105##
trans-4-((3-(2-Isopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.09 ##STR00106##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.10 ##STR00107##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 5.11 ##STR00108##
trans-4-(((trans-4-(5-Chloro-6-
methoxypyridin-3-yl)cyclohexyl)methyl)
(3-(1-cyclopropyl-1H-pyrazol-4-yl) phenyl)carbamoyl)cyclohexyl
methylcarbamate 5.12 ##STR00109##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.13 ##STR00110##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl
methylcarbamate 5.14 ##STR00111## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexyl methylcarbamate 5.15 ##STR00112##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(3-
(1-Isopropyl-1H-pyrazol-4- yl)phenyl)carbamoyl)cyclohexyl
methylcarbamate 5.16 ##STR00113##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(6-methoxy-5-
methylpyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.17 ##STR00114## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-cyclopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
methylcarbamate 5.18 ##STR00115## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
methylcarbamate 5.19 ##STR00116##
cis-4-(((4-(3-Cyano-4-methoxyphenyl)
cyclohexyl)methyl)(4-(1-isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)carbamoyl) cyclohexyl methylcarbamate
5.20 ##STR00117## trans-4-((3-(1-(tert-Butyl)-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.21 ##STR00118##
trans-4-((3-(1-Cyclobutyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.22 ##STR00119##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl dimethylcarbamate 5.23 ##STR00120##
trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(3-(1-cyclopropyl-1H-pyrazol-4-yl) phenyl)carbamoyl)cyclohexyl
methylcarbamate 5.24 ##STR00121##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.25 ##STR00122##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
ethylcarbamate 5.26 ##STR00123## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
methylcarbamate 5.27 ##STR00124## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(1-cyclopropyl-1H-pyrazol-4-yl)
pyridin-2-yl)carbamoyl)cyclohexyl methylcarbamate 5.28 ##STR00125##
trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl) carbamoyl)cyclohexyl
methylcarbamate 5.29 ##STR00126## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
ethylcarbamate 5.30 ##STR00127## trans-4-((3-(2-Isopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 5.31 ##STR00128##
trans-4-((3-(2-Isopropyloxazol-4- yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.32 ##STR00129##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.33 ##STR00130##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.34 ##STR00131##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.35 ##STR00132## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (2-cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl methylcarbamate 5.36 ##STR00133##
trans-4-((3-(6-(Dimethylamino)pyridine-
3-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 5.37 ##STR00134##
trans-4-((3-(6-Cyclopropylpyridin-3-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 5.38 ##STR00135##
trans-4-((3-(2-(Dimethylamino) pyrimidin-5-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl
methylcarbamate 5.39 ##STR00136## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropyloxazol-4-yl)pyridine-2- yl)carbamoyl)cyclohexyl
methylcarbamate 5.40 ##STR00137##
trans-4-((6-(Dimethylamino)-[3,4'-
bipyridin]-2'-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.41 ##STR00138##
trans-4-((3-(6-(Dimethylamino)pyridine-
3-yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.42 ##STR00139## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl) methyl)(3-(2-cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl methylcarbamate 5.43 ##STR00140##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.44 ##STR00141## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(2-cyclopropyloxazol-4-yl)pyridine- 2-yl)carbamoyl)cyclohexyl
methylcarbamate 5.45 ##STR00142## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-isopropyloxazol-4-yl)pyridine-2- yl)carbamoyl)cyclohexyl
methylcarbamate 5.46 ##STR00143## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl) (3-(2-isopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl methylcarbamate 5.47 ##STR00144##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
ethylcarbamate 5.48 ##STR00145##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
carbamate 5.49 ##STR00146## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl methyl
carbonate 5.50 ##STR00147## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)(trans-4-(6-methoxy-5-
methylpyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 5.51 ##STR00148##
trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-
2-yl)((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 5.52 ##STR00149##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)-1-methylcyclohexyl methylcarbamate 5.53 ##STR00150##
cis-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)-1-methylcyclohexyl methylcarbamate 6 ##STR00151##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
morpholine-4- carboxylate 6.01 ##STR00152##
4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)
((trans-4-(6-(dimethylamino)pyridin-3-
yl)cyclohexyl)methyl)carbamoyl) cyclohexyl (2-hydroxyethyl)trans-
carbamate 6.02 ##STR00153## trans-4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl) carbamate 6.03 ##STR00154##
trans-4-((4-(2-Isopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl) carbamate 6.04 ##STR00155##
trans-4-((3-(2-Isopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate 6.05 ##STR00156##
trans-4-(3-(2-Isopropylthiazol-5- yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate 6.06 ##STR00157##
trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(3-(2-cyclopropylthiazol-5-yl) phenyl)carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.07 ##STR00158##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate 6.08 ##STR00159##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate
6.09 ##STR00160## trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-hydroxyethyl) carbamate 6.10 ##STR00161##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-methoxyethyl) carbamate 6.11 ##STR00162##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (1,3- dihydroxypropan-2-yl)carbamate 6.12
##STR00163## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl ((S)-2,3- dihydroxypropyl)carbamate 6.13
##STR00164## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl ((R)-2,3- dihydroxypropyl)carbamate 6.14
##STR00165## trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (3- hydroxypropyl)carbamate 6.15 ##STR00166##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate 6.16 ##STR00167##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate 6.17 ##STR00168##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.18 ##STR00169##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (1- methylazetidin-3-yl)carbamate 6.19
##STR00170## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexyl (2- hydroxyethyl)carbamate 6.20
##STR00171## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-isopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexyl (2- hydroxyethyl)carbamate 6.21
##STR00172## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-cyclopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
(2- hydroxyethyl)carbamate 6.22 ##STR00173##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.23 ##STR00174##
trans-4-(((trans-4-(5-Chloro-6-
methoxypyridin-3-yl)cyclohexyl)methyl)
(3-(1-cyclopropyl-1H-pyrazol-4-yl) phenyl)carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.24 ##STR00175##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl oxetan-3- ylcarbamate 6.25 ##STR00176##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 4- methylpiperazine-1-carboxylate 6.26
##STR00177## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-methoxyethyl) (methyl)carbamate 6.27
##STR00178## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl thiomorpholine- 4-carboxylate 6.28
##STR00179## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(3-(1-cyclopropyl-1H-pyrazol-4-yl) phenyl)carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.29 ##STR00180##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- (methylsulfonyl)azetidine-1-carboxylate
6.30 ##STR00181## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-(methylthio) azetidine-1-carboxylate 6.31
##STR00182## trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
cyclopropylcarbamate 6.32 ##STR00183##
trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
isopropylcarbamate 6.33 ##STR00184## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)
(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
cyclopropylcarbamate 6.34 ##STR00185##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl (2-
methoxyethyl)carbamate 6.35 ##STR00186##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
cyclopropylcarbamate 6.36 ##STR00187##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl 3-
(methylsulfonyl)azetidine-1- carboxylate 6.37 ##STR00188##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
morpholine-4-carboxylate 6.38 ##STR00189##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl 4-
methylpiperazine-1-carboxylate 6.39 ##STR00190##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(methylsulfonyl)azetidine-1-carboxylate 6.40 ##STR00191##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
morpholine- 4-carboxylate 6.41 ##STR00192##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
methylpiperazine-1-carboxylate 6.42 ##STR00193##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(methylsulfonyl)azetidine-1- carboxylate 6.43 ##STR00194##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl)
carbamoyl)cyclohexylmorpholine-4- carboxylate 6.44 ##STR00195##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
methylpiperazine-1-carboxylate 6.45 ##STR00196##
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)
((4-(4-methoxy-3-methylphenyl)bicyclo
[2.2.2]octan-1-yl)methyl)carbamoyl) cyclohexyl
trans-(2-hydroxyethyl) carbamate 6.46 ##STR00197##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-hydroxyethyl) carbamate 6.47 ##STR00198##
trans-4-((3-(2-Isopropyloxazol-4- yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl) carbamate 6.48 ##STR00199##
trans-4-((3-(2-Isopropyloxazol-4- yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate 6.49 ##STR00200##
trans-4-((3-(2-Isopropyloxazol-4- yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate 6.50 ##STR00201##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate 6.51 ##STR00202##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(3-hydroxypropyl)carbamate 6.52 ##STR00203##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxyethyl) carbamate 6.53 ##STR00204##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(3-
(2-cyclopropyloxazol-4- yl)phenyl)carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.54 ##STR00205##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropyloxazol-4-yl)pyridine-2- yl)carbamoyl)cyclohexyl (2-
hydroxyethyl)carbamate 6.55 ##STR00206##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-cyclopropyloxazol-4- yl)phenyl)carbamoyl)cyclohexyl
(2- hydroxyethyl)carbamate 6.56 ##STR00207##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-methoxyethyl) carbamate 6.57 ##STR00208##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
cyclopropylcarbamate 6.58 ##STR00209##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
isopropylcarbamate 6.59 ##STR00210##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
morpholine- 4-carboxylate 6.60 ##STR00211##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
oxetan-3- ylcarbamate 6.61 ##STR00212##
trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)-N-((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)-4-(2-(3-(methylsulfonyl)
azetidin-1-yl)-2-oxoethyl) cyclohexanecarboxamide 6.62 ##STR00213##
trans-N-(4-(2-Cyclopropyloxazol-4-yl) pyridine-2-yl)-4-(2-((3-
hydroxypropyl)amino)-2-oxoethyl)-N-
((trans-4-(5-methoxy-6-methylpyridin- 2-yl)cyclohexyl)methyl)
cyclohexanecarboxamide 6.63 ##STR00214##
trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)-N-((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)-4-(2-((2-methoxyethyl)
(methyl)amino)-2-oxoethyl) cyclohexanecarboxamide 6.64 ##STR00215##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
methylpiperazine-1-carboxylate 6.65 ##STR00216##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
methylpiperazine-1-carboxylate 6.66 ##STR00217##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl ((S)-
2,3-dihydroxypropyl)carbamate 6.67 ##STR00218##
trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl(2- hydroxypropyl)(methyl)carbamate 6.68
##STR00219## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxy-2,3-dimethylbutyl)carbamate 6.69 ##STR00220##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxy-2-methylbutyl)carbamate 6.70 ##STR00221##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxy-2-methylpropyl)carbamate 6.71 ##STR00222##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (1-
hydroxypropan-2-yl)carbamate 6.72 ##STR00223##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxypropyl)carbamate 6.73 ##STR00224##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (3-
hydroxybutan-2-yl)carbamate 6.74 ##STR00225##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
ethyl(2-hydroxyethyl)carbamate 6.75 ##STR00226##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(methylsulfonyl)azetidine-1- carboxylate 6.76 ##STR00227##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-(2-
hydroxyethoxy)azetidine-1-carboxylate 6.77 ##STR00228##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
methylpiperazine-1-carboxylate 6.78 ##STR00229##
trans-4-(4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl)
carbamoyl)cyclohexylpiperazine-1- carboxylate 6.79 ##STR00230##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (1-
methylpiperidin-4-yl)carbamate 6.80 ##STR00231##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl ((R)-1-
methylpiperidin-3-yl)carbamate 6.81 ##STR00232##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
ethylpiperazine-1-carboxylate 6.82 ##STR00233##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 4-
isopropylpiperazine-1-carboxylate 6.83 ##STR00234##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 2,2-
dimethylmorpholine-4-carboxylate 6.84 ##STR00235##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
3-(oxetan-3-yl) azetidine-1-carboxylate 6.85 ##STR00236##
trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-
2-yl)((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2- hydroxyethyl)carbamate 6.86 ##STR00237##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxy-2- methylpropyl)(methyl)carbamate 6.87 ##STR00238##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (2-
hydroxyethyl)(methyl)carbamate 6.88 ##STR00239##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl (3-
hydroxypentan-2-yl)carbamate 6.89 ##STR00240##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxy-3- methylbutyl)carbamate 6.90 ##STR00241##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(1-hydroxy-2- methylpropan-2-yl)carbamate 6.91 ##STR00242##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl (2- hydroxy-2-methylpropyl)carbamate
6.92 ##STR00243## trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
(2-hydroxy-2- methylpropyl)carbamate 6.93 ##STR00244##
trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl ((S)-
1-hydroxypropan-2-yl)carbamate 6.94 ##STR00245##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy- 6-methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl ((R)- 1-hydroxypropan-2-yl)carbamate
6.95 ##STR00246## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl ((R)-
2-hydroxypropyl)carbamate 6.96 ##STR00247##
trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl ((S)-
2-hydroxypropyl)carbamate 7 ##STR00248##
trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridine-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.01 ##STR00249##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.02 ##STR00250##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- hydroxyazetidine-1-carboxylate 7.03
##STR00251## trans-4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.04 ##STR00252##
trans-4-((4-(2-Isopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.05 ##STR00253##
trans-4-((3-(2-Isopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.06 ##STR00254##
trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.07 ##STR00255##
trans-4-((4-(2-Isopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.08 ##STR00256##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropylthiazol-5-yl)pyridin-2- yl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.09 ##STR00257##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-cyclopropylthiazol-5- yl)phenyl)carbamoyl)cyclohexyl
3- hydroxyazetidine-1-carboxylate 7.10 ##STR00258##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(4-(2-cyclopropylthiazol-5-
yl)pyridin-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate 7.11 ##STR00259##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.12 ##STR00260##
4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- 3-hydroxyazetidine-1-carboxylate 7.13 ##STR00261##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol- 4-yl)phenyl)((trans-4-(6-
(dimethylamino)pyridin-3-yl) cyclohexyl)methyl)carbamoyl)
cyclohexyl 3-hydroxyazetidine-1- carboxylate 7.14 ##STR00262##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- hydroxyazetidine-1-carboxylate 7.15
##STR00263## trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.16 ##STR00264##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.17 ##STR00265## Methyl
2-((((trans-4-((3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl)oxy)
carbonyl)amino)acetate 7.18 ##STR00266##
2-((((trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl)oxy)
carbonyl)amino)acetic acid 7.19 ##STR00267##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(3-
(1-cyclopropyl-1H-pyrazol-4- yl)phenyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.20 ##STR00268##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(3-
(1-isopropyl-1H-pyrazol-4- yl)phenyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.21 ##STR00269##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-cyclopropyl-1H-pyrazol-4-yl) pyridin-2-yl)carbamoyl)cyclohexyl
3- hydroxyazetidine-1-carboxylate 7.22 ##STR00270##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.23 ##STR00271##
trans-4-(((trans-4-(5-Chloro-6- methoxypyridin-3-yl)cyclohexyl)
methyl)(3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)carbamoyl)
cyclohexyl 3-hydroxyazetidine-1- carboxylate 7.24 ##STR00272##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.25 ##STR00273##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(6-methoxy-5-
methylpyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.26 ##STR00274##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- (methoxymethyl)azetidine-1- carboxylate
7.27 ##STR00275## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- (dimethylamino)azetidine-1- carboxylate
7.28 ##STR00276## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- (hydroxymethyl)azetidine-1- carboxylate
7.29 ##STR00277## trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl
thiomorpholine-4-carboxylate 1-oxide 7.30 ##STR00278##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl thiomorpholine- 4-carboxylate1,1-dioxide 7.31
##STR00279## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl azetidine-1- carboxylate 7.32 ##STR00280##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- ((dimethylamino)methyl)azetidine-
1-carboxylate 7.33 ##STR00281## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl) methyl)(3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)carbamoyl) cyclohexyl 3-hydroxyazetidine-1-
carboxylate 7.34 ##STR00282## 1-(trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl) 3-
methylazetidine-1,3-dicarboxylate 7.35 ##STR00283##
1-(((trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl)oxy)
carbonyl)azetidine-3-carboxylic acid 7.36 ##STR00284##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-((tert- butoxycarbonyl)(methyl)amino)
azetidine-1-carboxylate 7.37 ##STR00285##
trans-4-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-(methylamino) azetidine-1-carboxylate 7.38
##STR00286## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-((tert- butoxycarbonyl)amino)azetidine-
1-carboxylate 7.39 ##STR00287##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- aminoazetidine-1-carboxylate 7.40
##STR00288## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl) methyl)(4-(1-isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)carbamoyl) cyclohexyl 3-hydroxyazetidine-1-
carboxylate 7.41 ##STR00289##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-(2-methoxy-2-
oxoethyl)azetidine-1-carboxylate 7.42 ##STR00290##
2-(1-(((trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl)oxy)
carbonyl)azetidin-3-yl)acetic acid 7.43 ##STR00291##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(1-isopropyl-1H-pyrazol- 4-yl)phenyl)carbamoyl)cyclohexyl
3- hydroxyazetidine-1-carboxylate 7.44 ##STR00292##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
isopropylcarbamate 7.45 ##STR00293## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
dimethylcarbamate 7.46 ##STR00294## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl
azetidine- 1-carboxylate 7.47 ##STR00295##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl 3-
ethylazetidine-1-carboxylate 7.48 ##STR00296##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl 3-
methoxyazetidine-1-carboxylate 7.49 ##STR00297##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin- 2-yl)carbamoyl)cyclohexyl 3-
isopropoxyazetidine-1-carboxylate 7.50 ##STR00298##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.51 ##STR00299##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl 3-
(hydroxymethyl)azetidine-1-carboxylate 7.52 ##STR00300##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
methoxyazetidine-1-carboxylate 7.53 ##STR00301##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.54 ##STR00302##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
ethylazetidine-1-carboxylate 7.55 ##STR00303##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
methoxyazetidine-1-carboxylate 7.56 ##STR00304##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
isopropoxyazetidine-1-carboxylate 7.57 ##STR00305##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
isopropylazetidine-1-carboxylate 7.58 ##STR00306##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.59 ##STR00307##
trans-4-((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl 3-
(hydroxymethyl)azetidine-1- carboxylate 7.60 ##STR00308##
trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl 3- ethylazetidine-1-carboxylate 7.61
##STR00309## trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(hydroxymethyl)azetidine-1- carboxylate 7.62 ##STR00310##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3-hydroxyazetidine-1-carboxylate 7.63
##STR00311## trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridine-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.64 ##STR00312##
trans-4-((3-(2-Isopropyloxazol-4- yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate 7.65 ##STR00313##
trans-4-((3-(2-Isopropyloxazol-4- yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.66 ##STR00314##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl 3- hydroxyazetidine-1-carboxylate 7.67
##STR00315## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate 7.68 ##STR00316##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(3-
(2-cyclopropyloxazol-4- yl)phenyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.69 ##STR00317##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropyloxazol-4-yl)pyridine-2- yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate 7.70 ##STR00318##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-cyclopropyloxazol-4- yl)phenyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.71 ##STR00319##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.72 ##STR00320##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(4-(2-cyclopropyloxazol-4-
yl)pyridine-2-yl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate 7.73 ##STR00321##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-
(2-isopropyloxazol-4-yl)pyridine-2- yl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.74 ##STR00322##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-isopropyloxazol-4- yl)phenyl)carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.75 ##STR00323##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
azetidine-1-carboxylate 7.76 ##STR00324##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
methoxyazetidine-1-carboxylate 7.77 ##STR00325##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(methoxymethyl)azetidine-1- carboxylate 7.78 ##STR00326##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
dimethylcarbamate 7.79 ##STR00327##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.80 ##STR00328##
trans-4-(4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(hydroxymethyl)azetidine-1- carboxylate 7.81 ##STR00329##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.82 ##STR00330##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
methoxyazetidine-1-carboxylate 7.83 ##STR00331##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
isopropoxyazetidine-1-carboxylate
7.84 ##STR00332## trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.85 ##STR00333##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
3-(2-methoxy-2- oxoethyl)azetidine-1-carboxylate 7.86 ##STR00334##
2-(1-(((trans-4-((4-(2- Cyclopropyloxazol-4-yl)pyridine-2-yl)
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)carbamoyl)
cyclohexyl)oxy)carbonyl)azetidin-3- yl)acetic acid 7.87
##STR00335## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
ethoxyazetidine-1-carboxylate 7.88 ##STR00336##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
cyanoazetidine-1-carboxylate 7.89 ##STR00337##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
methylazetidine-1-carboxylate 7.90 ##STR00338##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
ethylazetidine-1-carboxylate 7.91 ##STR00339##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
isopropoxyazetidine-1-carboxylate 7.92 ##STR00340##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(6-methoxy-5-
methylpyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(dimethylamino)azetidine-1- carboxylate 7.93 ##STR00341##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(6-methoxy-5-
methylpyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
methoxyazetidine-1-carboxylate 7.94 ##STR00342##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(6-methoxy-5-
methylpyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 7.95 ##STR00343##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(2-methoxyethoxy)azetidine-1- carboxylate 7.96 ##STR00344##
4-(4-(2-Cyclopropyloxazol-4-y)pyridine-
2-yl)((4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)
cyclohexyl-cis-3-hydroxyazetidine-1- carboxylate 7.97 ##STR00345##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(hydroxymethyl)azetidine-1- carboxylate 7.98 ##STR00346##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
ethynylazetidine-1-carboxylate 7.99 ##STR00347##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(2-hydroxypropan-2-yl)azetidine-1- carboxylate 7.100 ##STR00348##
trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
3-ethylazetidine- 1-carboxylate 7.101 ##STR00349##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
((methylsulfonyl)methyl)azetidine-1- carboxylate 7.102 ##STR00350##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
isopropylazetidine-1-carboxylate 7.103 ##STR00351##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
(tert-butyl)azetidine-1-carboxylate 7.104 ##STR00352##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridine-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
propoxyazetidine-1-carboxylate 7.105 ##STR00353##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
propylazetidine-1-carboxylate 7.106 ##STR00354##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
((dimethylamino)methyl)azetidine-1- carboxylate 7.107 ##STR00355##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 2-
methylmorpholine-4-carboxylate 7.108 ##STR00356##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl
3-hydroxy- [1,3'-biazetidine]-1'-carboxylate 7.109 ##STR00357##
trans-4-((4-(2-Ethyloxazol-4-yl)
pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl 3-
hydroxyazetidine-1-carboxylate 8 ##STR00358##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- ((methylsulfinyl)methyl)azetidine-1-
carboxylate 8.01 ##STR00359##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- (methylsulfinyl)azetidine-1-carboxylate 9
##STR00360## trans-4-((3-(1-cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl 3- ((methylsulfonyl)methyl)azetidine-1-
carboxylate 10 ##STR00361## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl trans-4- hydroxycyclohexanecarboxylate 11
##STR00362## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylamino)ethoxy)
cyclohexanecarboxamide hydrochloride 12 ##STR00363##
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)oxy)acetic acid 13 ##STR00364##
trans-4-(((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)(3-
(2-methoxythiazol-5- yl)phenyl)carbamoyl)cyclohexyl
dimethylcarbamate 13.01 ##STR00365##
trans-N-((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)-4-
(2-methoxyethoxy)-N-(3-(2- methoxythiazol-5-yl)phenyl)
cyclohexanecarboxamide 13.02 ##STR00366##
trans-N-((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)-4-
(3-methoxypropoxy)-N-(3-(2- methoxythiazol-5-yl)phenyl)
cyclohexanecarboxamide 13.03 ##STR00367##
trans-4-(2-Hydroxyethoxy)-N-((trans-4-
(4-methoxy-3-methylphenyl)cyclohexyl)
methyl)-N-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide
13.04 ##STR00368## trans-4-(3-Hydroxypropoxy)-N-((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)-N-(3-(2-
methoxythiazol-5-yl)phenyl) cyclohexanecarboxamide 13.05
##STR00369## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(2-(dimethylamino)ethoxy)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 14
##STR00370## Ethyl 2-(trans-4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(5- methoxy-6-methylpyridin-2-yl)
cyclohexyl)methyl)carbamoyl) cyclohexyl)acetate 15 ##STR00371##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-(hydroxymethyl)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 15.01 ##STR00372##
trans-4-(Hydroxymethyl)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)-N-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide
15.02 ##STR00373## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(hydroxymethyl)-N-((trans- 4-(4-methoxy-3-methylphenyl)
cyclohexyl)methyl) cyclohexanecarboxamide 15.03 ##STR00374##
trans-4-(Hydroxymethyl)-N-(4-(1-
isopropyl-1H-pyrazol-4-yl)pyridin-2- yl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) cyclohexanecarboxamide 15.04
##STR00375## trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)-4-(hydroxymethyl)-N-
((trans-4-(5-methoxy-6-methylpyridin- 2-yl)cyclohexyl)methyl)
cyclohexanecarboxamide 16 ##STR00376##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylic
acid 17 ##STR00377## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexanecarboxylic acid 17.01 ##STR00378##
trans-4-(((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)(3-
(2-methoxythiazol-5-yl)phenyl) carbamoyl)cyclohexanecarboxylic acid
17.02 ##STR00379## 4-(((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-yl)phenyl)
carbamoyl)bicyclo[2.2.2]octane-1- carboxylic acid 17.03
##STR00380## trans-4-(((trans-4-(3-Chloro-4-
methoxyphenyl)cyclohexyl)methyl)(3-
(2-cyclopropylthiazol-5-yl)phenyl) carbamoyl)cyclohexanecarboxylic
acid 17.04 ##STR00381## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(3-fluoro-1-methyl- 1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.05
##STR00382## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.06 ##STR00383##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((4-(6-(dimethylamino)
pyridin-3-yl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)
cyclohexanecarboxylic acid 17.07 ##STR00384##
trans-4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.08 ##STR00385##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.09
##STR00386## trans-4-((4-(2-Cyclopropylthiazol-5-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylic
acid 17.10 ##STR00387## trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylic acid 17.11 ##STR00388##
trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-
(2-4-cyclopropylthiazol-5-yl)phenyl)
carbamoyl)cyclohexanecarboxylic acid 17.12 ##STR00389##
trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-cyclopropylthiazol-5- yl)phenyl)carbamoyl)
cyclohexanecarboxylic acid 17.13 ##STR00390##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexanecarboxylic acid 17.14 ##STR00391##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol- 4-yl)phenyl)((trans-4-(6-
(dimethylamino)pyridin-3-yl) cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylic acid 17.15 ##STR00392##
trans-4-(((trans-4-(3-Chloro-4- methoxyphenyl)cyclohexyl)methyl)(3-
(1-cyclopropyl-1H-pyrazol-4- yl)phenyl)carbamoyl)
cyclohexanecarboxylic acid 17.16 ##STR00393##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(3-fluoro-1- methyl-1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.17
##STR00394## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.18 ##STR00395##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.19
##STR00396## trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)
cyclohexanecarboxylic acid 17.20 ##STR00397##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylic
acid 17.21 ##STR00398## trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(5-methoxy- 6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 17.22
##STR00399## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-
(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)
carbamoyl)cyclohexanecarboxylic acid 17.23 ##STR00400##
2-(trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-
methoxy-6-methylpyridin-2-yl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)acetic acid 17.24 ##STR00401##
2-(trans-4-((3-(1-Cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(5-
methoxy-6-methylpyridin-2-yl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)acetic acid 17.25 ##STR00402##
2-(trans-4-((4-(1-Isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl)
acetic acid 17.26 ##STR00403## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-
yl)carbamoyl)cyclohexyl)acetic acid 17.27 ##STR00404##
2-(trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(4-(1-isopropyl-1H-pyrazol- 4-yl)pyridin-2-yl)carbamoyl)
cyclohexyl)acetic acid 18 ##STR00405##
trans-4-(((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(3-
(2-cyclopropyloxazol-4-yl)phenyl) carbamoyl)cyclohexanecarboxylic
acid 18.01 ##STR00406## trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 18.02
##STR00407## trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridine-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylic
acid 18.03 ##STR00408## trans-4-((4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl) cyclohexanecarboxylic acid 18.04 ##STR00409##
trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(6-(dimethylamino) pyridine-3-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid 18.05
##STR00410## trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl) methyl)(3-(2-cyclopropyloxazol-4-
yl)phenyl)carbamoyl) cyclohexanecarboxylic acid 18.06 ##STR00411##
trans-Methyl 4-((3-(2- cyclopropylthiazol-5-yl)phenyl)((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylate 18.07 ##STR00412## trans-Methyl
4-(((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)(3-(2-
methoxythiazol-5-yl)phenyl) carbamoyl)cyclohexanecarboxylate 18.08
##STR00413## trans-Methyl 4-((3-(2-
cyclopropylthiazol-5-yl)phenyl)((trans-
4-(6-(dimethylamino)pyridin-3-yl) cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylate 18.09 ##STR00414## trans-Methyl
4-(((trans-4-(6-cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-cyclopropylthiazol-5- yl)phenyl)carbamoyl)
cyclohexanecarboxylate 18.10 ##STR00415## Methyl
4-(((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)(3-
(2-methoxythiazol-5-yl)phenyl) carbamoyl)bicyclo[2.2.2]octane-1-
carboxylate 18.11 ##STR00416## trans-4-(Benzyloxy)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)-N-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide
18.12 ##STR00417## trans-N-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- ((4-methoxybenzyl)oxy)-N-(3-(2-
methoxythiazol-5-yl)phenyl) cyclohexanecarboxamide 18.13
##STR00418## trans-Methyl 4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 18.14 ##STR00419## trans-Methyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(6-
(dimethylamino)pyridin-3- yl)cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylate 18.15 ##STR00420## tert-Butyl
(4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((4-(4-methoxy-
3-methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexyl) trans-carbamate 18.16 ##STR00421##
tert-Butyl (trans-4-((3-(1-isopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl)
carbamate 18.17 ##STR00422## trans-Methyl 4-((4-(1-cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 18.18
##STR00423## Ethyl 2-(trans-4-((4-(1-cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-
methoxy-6-methylpyridin-2-yl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)acetate 18.19 ##STR00424## trans-Methyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(5-
methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylate 18.20 ##STR00425## Ethyl
2-(trans-4-((4-(1-isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-
methoxy-6-methylpyridin-2-yl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)acetate 18.21 ##STR00426## Ethyl
2-(trans-4-(((trans-4-(3-cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin-
2-yl)carbamoyl)cyclohexyl)acetate 18.22 ##STR00427## Ethyl
2-(trans-4-(((trans-4-(6-cyano-5- methoxypyridin-2-yl)cyclohexyl)
methyl)(4-(1-isopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)carbamoyl)cyclohexyl) acetate 18.23 ##STR00428##
trans-Methyl 4-((4-(2- cyclopropyloxazol-4-yl)pyridin-2-yl)
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 18.24
##STR00429## trans-Methyl 4-(((trans-4-(6-cyano-5-
methoxypyridin-2-yl)cyclohexyl)
methyl)(3-(2-cyclopropyloxazol-4-yl) phenyl)carbamoyl)
cyclohexanecarboxylate 19 ##STR00430##
2-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)acetic acid 20 ##STR00431##
2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-
(2-cyclopropylthiazol-5-yl)phenyl) carbamoyl)cyclohexyl)acetic acid
20.01 ##STR00432## 2-(trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl) methyl)(3-(2-cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexyl) acetic acid 20.02 ##STR00433##
2-(trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic acid
20.03 ##STR00434## 2-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic
acid 20.04 ##STR00435## 2-(trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic
acid 20.05 ##STR00436## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropylthiazol-5-yl)pyridin-2-
yl)carbamoyl)cyclohexyl)acetic acid 20.06 ##STR00437##
2-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic acid
20.07 ##STR00438## 2-(trans-4-((3-(2-Isopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexyl) acetic acid 20.08 ##STR00439##
trans-2-(4-((4-(1-Cyclopropyl-1H- pyrazol-4-yl)pyridin-2-yl)((4-(4-
methoxy-3-methylphenyl)bicyclo [2.2.2]octan-1-yl)methyl)carbamoyl)
cyclohexyl)acetic acid 20.09 ##STR00440##
2-(trans-4-((3-(1-Cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)acetic acid 20.10 ##STR00441##
2-(trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)acetic acid 20.11 ##STR00442##
2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-cyclopropyl-1H-pyrazol-4-yl)
phenyl)carbamoyl)cyclohexyl)acetic acid 20.12 ##STR00443##
2-(trans-4-((3-(1-Cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(6-
(dimethylamino)pyridin-3-yl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)acetic acid 20.13 ##STR00444##
2-(trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic
acid 20.14 ##STR00445## 2-(trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)acetic acid 20.15 ##STR00446##
2-(trans-4-((4-(1-Isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic acid
20.16 ##STR00447## 3-(trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)propanoic acid 21 ##STR00448##
trans-2-(4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl)
acetic acid 21.01 ##STR00449##
2-(trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic
acid
21.02 ##STR00450## 2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)acetic acid 21.03 ##STR00451##
2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic
acid 21.04 ##STR00452## 2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((cis-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic
acid 21.05 ##STR00453## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-
(2-cyclopropyloxazol-4-yl)phenyl) carbamoyl)cyclohexyl)acetic acid
21.06 ##STR00454## 2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(6-(dimethylamino)
pyridin-3-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic acid
21.07 ##STR00455## 2-(trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl)
acetic acid 21.08 ##STR00456## 2-(trans-4-((3-(2-Isopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)acetic acid 21.09 ##STR00457##
2-(trans-4-((4-(2-Isopropyloxazol-4-yl)
pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic acid
21.10 ##STR00458## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (2-isopropyloxazol-4-yl)phenyl)
carbamoyl)cyclohexyl)acetic acid 21.11 ##STR00459##
2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-isopropyloxazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl)acetic
acid 21.12 ##STR00460## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropyloxazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl)acetic
acid 21.13 ##STR00461## 2-(trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl) methyl)(3-(2-cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl) acetic acid 22 ##STR00462##
trans-Propyl 4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 22.01 ##STR00463## trans-Isopropyl
4-((3-(1-cyclopropyl- 1H-pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 22.02 ##STR00464## trans-Butyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 22.03 ##STR00465## trans-Pentyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 22.04 ##STR00466## trans-Isobutyl
1H-pyrazol- 4-yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylate
22.05 ##STR00467## trans-Isopentyl 4-((3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 22.06 ##STR00468## trans-Propyl
4-((4-(1-cyclopropyl-1H- pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-
methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylate 23 ##STR00469##
trans-N1-(3-(1-cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N.sup.4-(2-hydroxyethyl)-N.sup.1-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)cyclohexane-
1,4-dicarboxamide 24 ##STR00470##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.1-
(3-(2-methoxythiazol-5-yl)phenyl)-N.sup.4-
methylcyclohexane-1,4-dicarboxamide 24.01 ##STR00471##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.1-
(3-(2-methoxythiazol-5-yl)phenyl) cyclohexane-1,4-dicarboxamide
24.02 ##STR00472## trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.1-
(3-(2-methoxythiazol-5-yl)phenyl)-
N.sup.4,N.sup.4-dimethylcyclohexane-1,4- dicarboxamide 24.03
##STR00473## trans-N.sup.1-(2-Hydroxyethyl)-N.sup.4-((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)-N.sup.4-(3-(2-
methoxythiazol-5-yl)phenyl) cyclohexane-1,4-dicarboxamide 24.04
##STR00474## trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.4-
(2-methoxyethyl)-N.sup.1-(3-(2- methoxythiazol-5-yl)phenyl)
cyclohexane-1,4-dicarboxamide 24.05 ##STR00475##
trans-N.sup.1-(2-(Dimethylamino)ethyl)-N.sup.4-
((trans-4-(4-methoxy-3-methylphenyl)
cyclohexyl)methyl)-N.sup.4-(3-(2- methoxythiazol-5-yl)phenyl)
cyclohexane-1,4-dicarboxamide 24.06 ##STR00476##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.1-
(3-(2-methoxythiazol-5-yl)phenyl)-
N.sup.4-(methylsulfonyl)cyclohexane-1,4- dicarboxamide 25
##STR00477## Methyl (trans-4-((3-(2-
cyclopropylthiazol-5-yl)phenyl)((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)carbamate 25.01 ##STR00478## tert-Butyl
(trans-4-(((trans-4-(4- methoxy-3-methylphenyl)cyclohexyl)
methyl)(3-(2-methoxythiazol-5-yl) phenyl)carbamoyl)cyclohexyl)
carbamate 25.02 ##STR00479## tert-Butyl ((trans-4-(((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)(3-(2-methoxythiazol-5-yl)
phenyl)carbamoyl)cyclohexyl)methyl) carbamate 25.03 ##STR00480##
trans-4-(Aminomethyl)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)-N-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide
25.04 ##STR00481## trans-4-Acetamido-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)-N-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide
25.05 ##STR00482## Methyl (trans-4-(((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-yl)phenyl)
carbamoyl)cyclohexyl)carbamate 25.06 ##STR00483##
trans-4-(Acetamidomethyl)-N-((trans- 4-(4-methoxy-3-methylphenyl)
cyclohexyl)methyl)-N-(3-(2- methoxythiazol-5-yl)phenyl)
cyclohexanecarboxamide 25.07 ##STR00484## Methyl
((trans-4-(((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-yl)
phenyl)carbamoyl)cyclohexyl)methyl) carbamate 25.08 ##STR00485##
trans-N-((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)-N-
(3-(2-methoxythiazol-5-yl)phenyl)-4- (methylsulfonamidomethyl)
cyclohexanecarboxamide 25.09 ##STR00486##
trans-4-Acetamido-N-(3-(2- cyclopropylthiazol-5-yl)phenyl)-N-
((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
cyclohexanecarboxamide 25.10 ##STR00487##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(N- methylacetamido)
cyclohexanecarboxamide 25.11 ##STR00488##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (methylsulfonamido)
cyclohexanecarboxamide 25.12 ##STR00489##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2-methoxyacetamido)
cyclohexanecarboxamide 25.13 ##STR00490##
2-((trans-4-((3-(2-Cyclopropylthiazol-
5-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)amino)-2- oxoethylacetate 25.14 ##STR00491##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(2-hydroxyacetamido)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 25.15 ##STR00492##
2-((trans-4-((3-(2-Cyclopropylthiazol-
5-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)amino)-2- oxoethyl methylcarbamate 25.16
##STR00493## trans-4-Butyramido-N-(3-(2-
cyclopropylthiazol-5-yl)phenyl)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 25.17 ##STR00494##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-
pentanamidocyclohexanecarboxamide 25.18 ##STR00495##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- methylbutanamido)
cyclohexanecarboxamide 26 ##STR00496##
Methyl(trans-4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)carbamate 26.01 ##STR00497##
trans-4-Acetamido-N-(3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
26.02 ##STR00498## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (methylsulfonamido)
cyclohexanecarboxamide 26.03 ##STR00499##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-(2-hydroxyacetamido)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.04
##STR00500## 2-((trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)amino)- 2-oxoethyl methylcarbamate
26.05 ##STR00501## 2-Hydroxyethyl(trans-4-((3-(1-
cyclopropyl-1H-pyrazol-4-yl)phenyl)
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)carbamate 26.06 ##STR00502##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol- 4-yl)phenyl)-4-(trans-4-
hydroxycyclohexanecarboxamido)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.07
##STR00503## trans-4-Acetamido-N-(3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)-N-((4-(4-
methoxy-3-methylphenyl)bicyclo[2.2.2] octan-1-yl)methyl)
cyclohexanecarboxamide 26.08 ##STR00504##
2-((4-((3-(1-Cyclopropyl-1H-pyrazol- 4-yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexyl)amino)- 2-oxoethyl trans-acetate
26.09 ##STR00505## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-(2-hydroxyacetamido)-
N-((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl)
cyclohexanecarboxamide 26.10 ##STR00506##
trans-4-Acetamido-N-(3-(1-isopropyl-
1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
26.11 ##STR00507## 2-((trans-4-(3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)amino)-2- oxoethyl acetate 26.12 ##STR00508##
trans-4-(2-Hydroxyacetamido)-N-(3-(1-
isopropyl-1H-pyrazol-4-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.13
##STR00509## trans-4-(Acetamidomethyl)-N-(3-(1-
cyclopropyl-1H-pyrazol-4-yl)phenyl)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.14
##STR00510## Methyl((trans-4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)methyl) carbamate 26.15 ##STR00511##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-
(methylsulfonamidomethyl) cyclohexanecarboxamide 26.16 ##STR00512##
trans-N-(3-(2-Cyopropyloxazol-4-yl)
phenyl)-4-(2-hydroxyacetamido)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 26.17 ##STR00513##
2-((trans-4-((4-(2-cyclopropyloxazol-4-
yl)pyridine-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)amino)-2-
oxoethyl acetate 26.18 ##STR00514##
trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)-4-(2-hydroxyacetamido)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.19
##STR00515## trans-4-Acetamido-N-(3-(2-
cyclopropyloxazol-4-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.20
##STR00516## trans-4-Acetamido-N-(4-(2-
cyclopropyloxazol-4-yl)pyridine-2-yl)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.21
##STR00517## Methyl (trans-4-((4-(2-
cyclopropyloxazol-4-yl)pyridine-2-yl)
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)carbamoyl) cyclohexyl)carbamate 26.22
##STR00518## trans-4-(Aminomethyl)-N-(4-(2-
cyclopropyloxazol-4-yl)pyridin-2-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin- 2-yl)cyclohexyl)methyl)
cyclohexanecarboxamide 26.23 ##STR00519##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2- acetamidoethyl)carbamate 26.24
##STR00520## trans-4-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2- (methylsulfonamido)ethyl)carbamate 26.25
##STR00521## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexylmethylethane- 1,2-diyldicarbamate 26.26
##STR00522## trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)-N-((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl)
methyl)-4-(methylsulfonamidomethyl) cyclohexanecarboxamide 26.27
##STR00523## Methyl ((trans-4-((4-(2-
cyclopropyloxazol-4-yl)pyridin-2-yl)
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)carbamoyl) cyclohexyl)methyl)carbamate 26.28
##STR00524## Ethyl ((trans-4-((4-(2-cyclopropyloxazol-
4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)methyl)carbamate 26.29 ##STR00525##
trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)-4-((2-hydroxyacetamido)
methyl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) cyclohexanecarboxamide 26.30
##STR00526## trans-4-Acetamido-N-(4-(1-cyclopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.31
##STR00527## 2-((trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)amino)- 2-oxoethyl acetate 26.32
##STR00528## trans-N-(4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)-4-(2- hydroxyacetamido)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
26.33 ##STR00529## trans-4-Acetamido-N-(4-(1-isopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 26.34 ##STR00530##
2-((trans-4-((4-(1-Isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)amino)-2-
oxoethyl acetate 26.35 ##STR00531##
trans-4-(2-Hydroxyacetamido)-N-(4-(1-
isopropyl-1H-pyrazol-4-yl)pyridin-2- yl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 26.36
##STR00532## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3-
methylureido)cyclohexanecarboxamide 26.37 ##STR00533##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3-
methylureido)cyclohexanecarboxamide 27 ##STR00534##
trans-N-(3-(2-Cyclopropylthiazol-5-yl) phenyl)-4-(2-hydroxy-2-
methylpropanamido)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
27.01 ##STR00535## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(2-hydroxypropanamido)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 27.02
##STR00536## N-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)oxetane-3- carboxamide 27.03 ##STR00537##
trans-4-(2-(1H-Imidazol-1-yl)acetamido)-
N-(3-(2-cyclopropylthiazol-5-yl)phenyl)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 27.04
##STR00538## trans-4-(2-(1H-Imidazol-2-yl)acetamido)-
N-(3-(2-cyclopropylthiazol-5-yl)phenyl)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 27.05
##STR00539## N-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)-1- methylazetidine-3-carboxamide 27.06
##STR00540## N-(trans-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)azetidine-3- carboxamide 28 ##STR00541##
2-Hydroxyethyl(trans-4-((3-(2-
cyclopropylthiazol-5-yl)phenyl)((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)carbamate 29 ##STR00542##
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)amino)acetic acid 30 ##STR00543##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3-
methoxycyclobutanecarboxamido) cyclohexanecarboxamide 30.01
##STR00544## trans-4-(Cyclobutanecarboxamido)-N-(3-
(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 30.02
##STR00545## trans-4-(cyclobutanecarboxamido)-trans-
(4-(2-cyclopropyloxazol-4-yl)pyridine-
2-yl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) cyclohexanecarboxamide 30.03
##STR00546## trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl)-
4-(3-methoxycyclobutanecarboxamido) cyclohexanecarboxamide 30.04
##STR00547## trans-4- (Cyclobutanecarboxamidomethyl)-N-
(4-(2-cyclopropyloxazol-4-yl)pyridin-2-
yl)-N-((trans-4-(5-methoxy-6- methylpyridin-2-yl)cyclohexyl)methyl)
cyclohexanecarboxamide 30.05 ##STR00548##
trans-N-(4-(2-Cyclopropyloxazol-4-yl)
pyridin-2-yl)-4-((3-(dimethylamino)
cyclobutanecarboxamido)methyl)-N-
((trans-4-(5-methoxy-6-methylpyridin- 2-yl)cyclohexyl)methyl)
cyclohexanecarboxamide 30.06 ##STR00549##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2-(methylsulfonamido)acetamido)
cyclohexanecarboxamide 31 ##STR00550## Methyl
(2-((trans-4-((3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)amino)- 2-oxoethyl)carbamate 31.01
##STR00551## trans-4-(2-Acetamidoacetamido)-N-(3-
(1-cyclopropyl-1H-pyrazol-4-yl) phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 31.02
##STR00552## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfonyl)acetamido)
cyclohexanecarboxamide 31.03 ##STR00553##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfonamido)acetamido)
cyclohexanecarboxamide 31.04 ##STR00554##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfinyl)acetamido)
cyclohexanecarboxamide 31.05 ##STR00555## Methyl
(2-((trans-4-((3-(2- cyclopropylthiazol-5-yl)phenyl)((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)carbamoyl)
cyclohexyl)amino)-2-oxoethyl) carbamate 31.06 ##STR00556##
trans-N-(3-(2-Cyclopropylthiazol-5-yl) phenyl)-4-(2-(dimethylamino)
acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 31.07
##STR00557## trans-4-(2-Aminoacetamido)-N-(3-(2-
cyclopropylthiazol-5-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 31.08
##STR00558## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylamino)acetamido)
cyclohexanecarboxamide 31.09 ##STR00559##
trans-4-(2-Acetamidoacetamido)-N-(3-
(2-cyclopropylthiazol-5-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 31.10
##STR00560## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylthio)acetamido)
cyclohexanecarboxamide 31.11 ##STR00561##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2-(methylsulfinyl)acetamido)
cyclohexanecarboxamide 31.12 ##STR00562##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2-(methylsulfonyl)acetamido)
cyclohexanecarboxamide 31.13 ##STR00563##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- (methylsulfinyl)propanamido)
cyclohexanecarboxamide 31.14 ##STR00564##
trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- (methylsulfonyl)propanamido)
cyclohexanecarboxamide 31.15 ##STR00565##
trans-4-(2-(1H-Imidazol-4-yl)
acetamido)-N-(3-(2-cyclopropylthiazol-
5-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 32
##STR00566## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-(2-(3-hydroxypropoxy)
acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 32.01
##STR00567## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-(2-(2-hydroxyethoxy)
acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 32.02
##STR00568## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(2-(2-hydroxyethoxy) acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 32.03
##STR00569## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(2-(3-hydroxypropoxy)
acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 32.04
##STR00570## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-4-(2-(2-(dimethylamino)ethoxy)
acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide
32.05 ##STR00571## trans-4-(2-(2-Aminoethoxy)acetamido)-
N-(3-(2-cyclopropylthiazol-5-yl) phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 32.06
##STR00572## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2-
(2-(methylamino)ethoxy)acetamido) cyclohexanecarboxamide 33
##STR00573## trans-N-(3-(2-Cyclopropylthiazol-5-yl)
phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2H-tetrazol-5-yl)
cyclohexanecarboxamide 33.01 ##STR00574##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2H-tetrazol-5-yl)
cyclohexanecarboxamide 34 ##STR00575##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(5-
oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)cyclohexanecarboxamide
[0289] In some embodiments, provided herein is a pharmaceutically
acceptable salt or solvate of a compound that is described in Table
1.
TABLE-US-00002 TABLE 2 Structure Chemical Name ##STR00576##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-
2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclohexyl(2-
hydroxybutyl)(methyl)carbamate ##STR00577##
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-
2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclohexyl(2-
hydroxy-3-methylbutyl)(methyl)carbamate
[0290] In some embodiments, provided herein is a pharmaceutically
acceptable salt or solvate of a compound that is described in Table
2.
[0291] In one aspect, compounds described herein are in the form of
pharmaceutically acceptable salts. As well, active metabolites of
these compounds having the same type of activity are included in
the scope of the present disclosure. In addition, the compounds
described herein can exist in unsolvated as well as solvated forms
with pharmaceutically acceptable solvents such as water, ethanol,
and the like. The solvated forms of the compounds presented herein
are also considered to be disclosed herein.
[0292] "Pharmaceutically acceptable," as used herein, refers a
material, such as a carrier or diluent, which does not abrogate the
biological activity or properties of the compound, and is
relatively nontoxic, i.e., the material is administered to an
individual without causing undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[0293] The term "pharmaceutically acceptable salt" refers to a form
of a therapeutically active agent that consists of a cationic form
of the therapeutically active agent in combination with a suitable
anion, or in alternative embodiments, an anionic form of the
therapeutically active agent in combination with a suitable cation.
Handbook of Pharmaceutical Salts: Properties, Selection and Use.
International Union of Pure and Applied Chemistry, Wiley-VCH 2002.
S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977,
66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of
Pharmaceutical Salts: Properties, Selection and Use,
Weinheim/Zurich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts
typically are more soluble and more rapidly soluble in stomach and
intestinal juices than non-ionic species and so are useful in solid
dosage forms. Furthermore, because their solubility often is a
function of pH, selective dissolution in one or another part of the
digestive tract is possible, and this capability can be manipulated
as one aspect of delayed and sustained release behaviors. Also,
because the salt-forming molecule can be in equilibrium with a
neutral form, passage through biological membranes can be
adjusted.
[0294] In some embodiments, pharmaceutically acceptable salts are
obtained by reacting a compound described herein with an acid to
provide a "pharmaceutically acceptable acid addition salt." In some
embodiments, the compound described herein (i.e. free base form) is
basic and is reacted with an organic acid or an inorganic acid.
Inorganic acids include, but are not limited to, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
metaphosphoric acid. Organic acids include, but are not limited to,
1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid;
2-hydroxyethanesulfonic acid; 2-oxoglutaric acid;
4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic
acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid;
benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+);
capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic
acid (octanoic acid); carbonic acid; cinnamic acid; citric acid;
cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid;
ethanesulfonic acid; formic acid; fumaric acid; galactaric acid;
gentisic acid; glucoheptonic acid (D); gluconic acid (D);
glucuronic acid (D); glutamic acid; glutaric acid;
glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric
acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid;
malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic
acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid;
naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic
acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid;
pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid;
succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid;
toluenesulfonic acid (p); and undecylenic acid.
[0295] In some embodiments, a compound described herein is prepared
as a chloride salt, sulfate salt, bromide salt, mesylate salt,
maleate salt, citrate salt or phosphate salt.
[0296] In some embodiments, pharmaceutically acceptable salts are
obtained by reacting a compound described herein with a base to
provide a "pharmaceutically acceptable base addition salt."
[0297] In some embodiments, the compound described herein is acidic
and is reacted with a base. In such situations, an acidic proton of
the compound described herein is replaced by a metal ion, e.g.,
lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
In some cases, compounds described herein coordinate with an
organic base, such as, but not limited to, ethanolamine,
diethanolamine, triethanolamine, tromethamine, meglumine,
N-methylglucamine, dicyclohexylamine,
tris(hydroxymethyl)methylamine. In other cases, compounds described
herein form salts with amino acids such as, but not limited to,
arginine, lysine, and the like. Acceptable inorganic bases used to
form salts with compounds that include an acidic proton, include,
but are not limited to, aluminum hydroxide, calcium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, sodium
hydroxide, lithium hydroxide, and the like. In some embodiments,
the compounds provided herein are prepared as a sodium salt,
calcium salt, potassium salt, magnesium salt, meglumine salt,
N-methylglucamine salt or ammonium salt.
[0298] It should be understood that a reference to a
pharmaceutically acceptable salt includes the solvent addition
forms. In some embodiments, solvates contain either stoichiometric
or non-stoichiometric amounts of a solvent, and are formed during
the process of isolating or purifying the compound with
pharmaceutically acceptable solvents such as water, ethanol, and
the like. Hydrates are formed when the solvent is water, or
alcoholates are formed when the solvent is alcohol. Solvates of
compounds described herein are conveniently prepared or formed
during the processes described herein. In addition, the compounds
provided herein optionally exist in unsolvated as well as solvated
forms.
[0299] The methods and formulations described herein include the
use of N-oxides (if appropriate), crystalline forms (also known as
polymorphs), or pharmaceutically acceptable salts of compounds
described herein, as well as active metabolites of these compounds
having the same type of activity.
[0300] In some embodiments, sites on the organic groups (e.g. alkyl
groups, aromatic rings) of compounds described herein are
susceptible to various metabolic reactions. Incorporation of
appropriate substituents on the organic groups will reduce,
minimize or eliminate this metabolic pathway. In specific
embodiments, the appropriate substituent to decrease or eliminate
the susceptibility of the aromatic ring to metabolic reactions is,
by way of example only, a halogen, deuterium, an alkyl group, a
haloalkyl group, or a deuteroalkyl group.
[0301] In another embodiment, the compounds described herein are
labeled isotopically (e.g. with a radioisotope) or by another other
means, including, but not limited to, the use of chromophores or
fluorescent moieties, bioluminescent labels, or chemiluminescent
labels.
[0302] Compounds described herein include isotopically-labeled
compounds, which are identical to those recited in the various
formulae and structures presented herein, but for the fact that one
or more atoms are replaced by an atom having an atomic mass or mass
number different from the atomic mass or mass number usually found
in nature. Examples of isotopes that can be incorporated into the
present compounds include isotopes of hydrogen, carbon, nitrogen,
oxygen, fluorine and chlorine, such as, for example, .sup.2H,
.sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.35S, .sup.18F, .sup.36Cl. In one aspect, isotopically-labeled
compounds described herein, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays. In
one aspect, substitution with isotopes such as deuterium affords
certain therapeutic advantages resulting from greater metabolic
stability, such as, for example, increased in vivo half-life or
reduced dosage requirements. In some embodiments, one or more
hydrogen atoms of the compounds described herein is replaced with
deuterium.
[0303] In some embodiments, the compounds described herein possess
one or more stereocenters and each stereocenter exists
independently in either the R or S configuration. The compounds
presented herein include all diastereomeric, enantiomeric,
atropisomers, and epimeric forms as well as the appropriate
mixtures thereof. The compounds and methods provided herein include
all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers
as well as the appropriate mixtures thereof.
[0304] Individual stereoisomers are obtained, if desired, by
methods such as, stereoselective synthesis and/or the separation of
stereoisomers by chiral chromatographic columns. In certain
embodiments, compounds described herein are prepared as their
individual stereoisomers by reacting a racemic mixture of the
compound with an optically active resolving agent to form a pair of
diastereoisomeric compounds/salts, separating the diastereomers and
recovering the optically pure enantiomers. In some embodiments,
resolution of enantiomers is carried out using covalent
diastereomeric derivatives of the compounds described herein. In
another embodiment, diastereomers are separated by
separation/resolution techniques based upon differences in
solubility. In other embodiments, separation of steroisomers is
performed by chromatography or by the forming diastereomeric salts
and separation by recrystallization, or chromatography, or any
combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen,
"Enantiomers, Racemates and Resolutions", John Wiley and Sons,
Inc., 1981. In some embodiments, stereoisomers are obtained by
stereoselective synthesis.
[0305] In some embodiments, compounds described herein are prepared
as prodrugs. A "prodrug" refers to an agent that is converted into
the parent drug in vivo. Prodrugs are often useful because, in some
situations, they are easier to administer than the parent drug.
They are, for instance, bioavailable by oral administration whereas
the parent is not. The prodrug may be a substrate for a
transporter. Further or alternatively, the prodrug also has
improved solubility in pharmaceutical compositions over the parent
drug. In some embodiments, the design of a prodrug increases the
effective water solubility. An example, without limitation, of a
prodrug is a compound described herein, which is administered as an
ester (the "prodrug") but then is metabolically hydrolyzed to
provide the active entity. A further example of a prodrug is a
short peptide (polyaminoacid) bonded to an acid group where the
peptide is metabolized to reveal the active moiety. In certain
embodiments, upon in vivo administration, a prodrug is chemically
converted to the biologically, pharmaceutically or therapeutically
active form of the compound. In certain embodiments, a prodrug is
enzymatically metabolized by one or more steps or processes to the
biologically, pharmaceutically or therapeutically active form of
the compound.
[0306] Prodrugs of the compounds described herein include, but are
not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl
derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of
tertiary amines, N-Mannich bases, Schiff bases, amino acid
conjugates, phosphate esters, and sulfonate esters. See for example
Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in
Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p.
309-396; Bundgaard, H. "Design and Application of Prodrugs" in A
Textbook of Drug Design and Development, Krosgaard-Larsen and H.
Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H.,
Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is
incorporated herein by reference. In some embodiments, a hydroxyl
group in the compounds disclosed herein is used to form a prodrug,
wherein the hydroxyl group is incorporated into an acyloxyalkyl
ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester,
phosphate ester, sugar ester, ether, and the like. In some
embodiments, a hydroxyl group in the compounds disclosed herein is
a prodrug wherein the hydroxyl is then metabolized in vivo to
provide a carboxylic acid group. In some embodiments, a carboxyl
group is used to provide an ester or amide (i.e. the prodrug),
which is then metabolized in vivo to provide a carboxylic acid
group. In some embodiments, compounds described herein are prepared
as alkyl ester prodrugs.
[0307] Prodrug forms of the herein described compounds, wherein the
prodrug is metabolized in vivo to produce a compound described
herein as set forth herein are included within the scope of the
claims. In some cases, some of the herein-described compounds is a
prodrug for another derivative or active compound. In some
embodiments, a prodrug of the compound disclosed herein permits
targeted delivery of the compound to a particular region of the
gastrointestinal tract. Formation of a pharmacologically active
metabolite by the colonic metabolism of drugs is a commonly used
"prodrug" approach for the colon-specific drug delivery
systems.
[0308] In some embodiments, a prodrug is formed by the formation of
a covalent linkage between drug and a carrier in such a manner that
upon oral administration the moiety remains intact in the stomach
and small intestine. This approach involves the formation of
prodrug, which is a pharmacologically inactive derivative of a
parent drug molecule that requires spontaneous or enzymatic
transformation in the biological environment to release the active
drug. Formation of prodrugs has improved delivery properties over
the parent drug molecule. The problem of stability of certain drugs
from the adverse environment of the upper gastrointestinal tract
can be eliminated by prodrug formation, which is converted into
parent drug molecule once it reaches into the colon. Site specific
drug delivery through site specific prodrug activation may be
accomplished by the utilization of some specific property at the
target site, such as altered pH or high activity of certain enzymes
relative to the non-target tissues for the prodrug-drug
conversion.
[0309] In some embodiments, covalent linkage of the drug with a
carrier forms a conjugate conjugate. Such conjugates include, but
are not limited to, azo bond conjugates, glycoside conjugates,
glucuronide conjugates, cyclodextrin conjugates, dextran conjugates
or amino-acid conjugates.
[0310] In additional or further embodiments, the compounds
described herein are metabolized upon administration to an organism
in need to produce a metabolite that is then used to produce a
desired effect, including a desired therapeutic effect.
[0311] A "metabolite" of a compound disclosed herein is a
derivative of that compound that is formed when the compound is
metabolized. The term "active metabolite" refers to a biologically
active derivative of a compound that is formed when the compound is
metabolized. The term "metabolized," as used herein, refers to the
sum of the processes (including, but not limited to, hydrolysis
reactions and reactions catalyzed by enzymes) by which a particular
substance is changed by an organism. Thus, enzymes may produce
specific structural alterations to a compound. For example,
cytochrome P450 catalyzes a variety of oxidative and reductive
reactions while uridine diphosphate glucuronyltransferases catalyze
the transfer of an activated glucuronic-acid molecule to aromatic
alcohols, aliphatic alcohols, carboxylic acids, amines and free
sulphydryl groups. Metabolites of the compounds disclosed herein
are optionally identified either by administration of compounds to
a host and analysis of tissue samples from the host, or by
incubation of compounds with hepatic cells in vitro and analysis of
the resulting compounds.
[0312] In some embodiments, the compounds described herein are
rapidly metabolized following absorption from the gastro-intestinal
tract to metabolites that have greatly reduced FXR agonist
activity.
[0313] In additional or further embodiments, the compounds are
rapidly metabolized in plasma.
[0314] In additional or further embodiments, the compounds are
rapidly metabolized by the intestines.
[0315] In additional or further embodiments, the compounds are
rapidly metabolized by the liver.
Synthesis of Compounds
[0316] Compounds described herein are synthesized using standard
synthetic techniques or using methods known in the art in
combination with methods described herein.
[0317] Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology are employed.
[0318] Compounds are prepared using standard organic chemistry
techniques such as those described in, for example, March's
Advanced Organic Chemistry, 6.sup.th Edition, John Wiley and Sons,
Inc. Alternative reaction conditions for the synthetic
transformations described herein may be employed such as variation
of solvent, reaction temperature, reaction time, as well as
different chemical reagents and other reaction conditions. The
starting materials are available from commercial sources or are
readily prepared.
[0319] Suitable reference books and treatise that detail the
synthesis of reactants useful in the preparation of compounds
described herein, or provide references to articles that describe
the preparation, include for example, "Synthetic Organic
Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et
al., "Organic Functional Group Preparations," 2nd Ed., Academic
Press, New York, 1983; H. O. House, "Modem Synthetic Reactions",
2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.
Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley &
Sons, New York, 1992; J. March, "Advanced Organic Chemistry:
Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience,
New York, 1992. Additional suitable reference books and treatise
that detail the synthesis of reactants useful in the preparation of
compounds described herein, or provide references to articles that
describe the preparation, include for example, Fuhrhop, J. and
Penzlin G. "Organic Synthesis: Concepts, Methods, Starting
Materials", Second, Revised and Enlarged Edition (1994) John Wiley
& Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry,
An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;
Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John
Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C.,
"Intermediate Organic Chemistry" 2nd Edition (1993)
Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann's
Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in
8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons,
in over 55 volumes; and "Chemistry of Functional Groups" John Wiley
& Sons, in 73 volumes.
[0320] The compounds described herein are prepared by the general
synthetic routes described below in Schemes 1 to 16.
[0321] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
1.
##STR00578##
[0322] In Scheme 1, substituents X.sup.2, X.sup.3 X.sup.4, R.sup.1,
and R.sup.2 are as described herein. In some embodiments, X.sup.2
is C--R.sup.2, X.sup.3 is C--H, and each X.sup.4 is C--H. In some
embodiments, X is a halide. In some embodiments, X is chloro,
bromo, or iodo.
[0323] In some embodiments, boronic ester I-2 is reacted with
halide I-1 under suitable metal-catalyzed cross-coupling reaction
conditions to provide I-3. In some embodiments, suitable
metal-catalyzed cross-coupling conditions include the use of
palladium. In some embodiments, suitable palladium-catalyzed
cross-coupling reaction conditions include Pd(dppf)Cl.sub.2 or
Pd(PPh.sub.3).sub.4 with an appropriate base, with an appropriate
solvent or solvent mixture for an appropriate time and at an
appropriate temperature. In some embodiments, the base is an
inorganic base. In some embodiments, the inorganic base is a
carbonate base such as Na.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. In
some embodiments, the appropriate solvent or solvent mixture is
dioxane, acetonitrile, DME/EtOH, or ethanol. In some embodiments,
the appropriate time and appropriate temperature is about 2 to
about 18 hours (overnight) hours at about 50.degree. C. or about
100.degree. C.
[0324] In some embodiments, 1-3 is subjected to suitable
hydrogenation conditions followed by treatment under appropriate
acidic conditions to provide cyclohexanone I-4. In some
embodiments, suitable hydrogenation conditions include the use of
palladium. Palladium-catalyzed hydrogenation conditions include the
use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such
as EtOAc, ethanol, methanol or a combination of these solvents, for
an appropriate amount of time at an appropriate temperature. In
some embodiments, the appropriate amount of time is about 4.5 hours
to about 18 hours (overnight) at about rt. In some embodiments,
appropriate acidic conditions include formic acid in water and
toluene for a suitable amount of time at an appropriate
temperature. In some embodiments, the suitable amount of time at an
appropriate temperature is about 4 hours at about 120.degree. C. In
some embodiments, the suitable amount of time at an appropriate
temperature is about 18 hours (overnight) at reflux. In some
embodiments, appropriate acidic conditions include PPTS in acetone
and water for a suitable amount of time at an appropriate
temperature. In some embodiments, the suitable amount of time at an
appropriate temperature is about 10 hours at about 60.degree. C. In
some embodiments, appropriate acidic conditions include 3 M HCl and
THF for a suitable amount of time at an appropriate temperature. In
some embodiments, the suitable amount of time at an appropriate
temperature is about 3 hours to about overnight at about 60.degree.
C.
[0325] In some embodiments, I-4 is reacted under suitable one
carbon-homologation conditions to provide I-5. In some embodiments,
suitable one carbon-homologation conditions include the use of
phosphonium reagents. In some embodiments, suitable
one-carbon-homologation conditions, includes pre-treating
(methoxymethyl)triphenyl phosphonium chloride
[Ph.sub.3P.sup.+CH.sub.2OCH.sub.3Cl.sup.-] with an appropriate
base, with an appropriate solvent for an appropriate amount of time
at an appropriate temperature before the addition of cyclohexanone
I-4. In some embodiments, the appropriate base is NaHMDS. In some
embodiments, the appropriate base is KHMDS or LiHMDS. In some
embodiments, the appropriate solvent is THF. In some embodiments,
the appropriate amount of time before addition of cyclohexanone I-4
at an appropriate temperature is about 30 mins to about 2 hours at
about 0.degree. C. In some embodiments, after I-4 is added the
reaction is continued for an additional about 30 mins to about 3
hours at about 0.degree. C. In some embodiments, the reaction is
allowed to warm to about room temperature overnight.
[0326] In some embodiments, I-5 is then subjected under suitable
acidic conditions to provide a mixture of cis and trans aldehydes
I-6. In some embodiments, suitable acidic conditions include formic
acid in water/toluene at about 120.degree. C. to about 130.degree.
C. for about 2 hours to about overnight. In some embodiments,
suitable acidic conditions include HCl in THF at about 60.degree.
C. for about 1 hour or about 6 hours. In some embodiments, further
subjection of aldehyde I-6 under appropriate basic conditions
provides a mostly trans aldehyde I-6. In some embodiments,
appropriate basic conditions include NaOH in a suitable solvent
mixture, such as H.sub.2O, EtOH and PhMe, for an appropriate amount
of time at an appropriate temperature. In some embodiments, THF is
used instead of PhMe. In some embodiments, the appropriate amount
of time at an appropriate temperature is about 5.5 hours to about
overnight at about rt. In some embodiments, appropriate basic
conditions include NaOMe in a suitable solvent, such as MeOH, for
an appropriate amount of time at an appropriate temperature. In
some embodiments, the appropriate amount of time at an appropriate
temperature is at about 4 hours to about 18 hours at about room
temperature. In some embodiments, further purification via
crystallization or chromatography provides pure trans aldehyde
I-6.
[0327] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
2.
##STR00579##
[0328] In Scheme 2, substituents X.sup.2, X.sup.3, X.sup.4,
R.sup.1, R.sup.2, and m are as described herein. In some
embodiments, X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each
X.sup.4 is C--H. In some embodiments, R.sup.6 is alkyl. In some
embodiments, R.sup.6 is methyl. In some embodiments, X is a
halogen. In some embodiments, X is chloro, bromo, or iodo.
[0329] In some embodiments, II-1 is cooled to a suitable
temperature, reacted under suitable metal-halogen exchange
conditions with an appropriate solvent for an appropriate time and
at an appropriate temperature, and then later reacted with an
appropriate ketone I-2 for an appropriate time and at an
appropriate temperature to provide II-3. In some embodiments,
suitable metal-halogen exchange conditions include an
organometallic reagent. In some embodiments, an appropriate solvent
is THF. In some embodiments, the organometallic reagent is an alkyl
lithium. In some embodiments, the alkylithium is n-butyl lithium.
In some embodiments, II-1 is cooled to about -78.degree. C. before
addition of an organometallic reagent. In some embodiments, II-1 is
reacted for about two hours at about -78.degree. C. before addition
of the appropriate ketone II-2. In some embodiments, the
intermediate organometallic reagent is reacted for about 3 hours
after addition of ketone II-2. In some embodiments, the
intermediate organometallic reagent is reacted at about -78.degree.
C. after addition of ketone II-2.
[0330] In some embodiments, alcohol II-3 is reacted under
appropriate reduction conditions with an appropriate solvent for an
appropriate time and at an appropriate temperature to form a
mixture of dehydrated and reduced products. In some embodiments,
conditions include the use of trifluoracetic acid and a silyl
hydride. In some embodiments, the silyl hydride is triethylsilane.
In some embodiments, the appropriate solvent is dichloromethane. In
some embodiments, the temperature is about 0.degree. C. to about rt
or about 0.degree. C. In some embodiments, the appropriate time is
about overnight or about 1 hour. In some embodiments, the mixture
of reduced and dehydrated products is reacted under the appropriate
conditions with an appropriate solvent for an appropriate time and
at an appropriate temperature to form a ketone. In some
embodiments, the appropriate solvent is a formic acid, toluene, and
water mixture. In some embodiments, the appropriate temperature is
about 130.degree. C. In some embodiments, the appropriate time is
about overnight. In some embodiments, the appropriate solvent is a
formic acid, THF, and water mixture. In some embodiments, the
appropriate temperature is about 80.degree. C. In some embodiments,
the appropriate time is about 18 hours. In some embodiments, this
ketone, containing the dehydrated side product, is fully reduced
under suitable reduction conditions with an appropriate solvent for
an appropriate time and at an appropriate temperature to form II-4.
In some embodiments, the appropriate reduction conditions include
the use of hydrogen as a reducing agent. In some embodiments, the
hydrogen is at a pressure of about 15 psi or about 30 psi. In some
embodiments, the alkene reduction includes use of a palladium
catalyst. In some embodiments, the palladium catalyst is 10%
palladium on carbon. In some embodiments, the solvent is ethyl
acetate and concentrated HCl. In some embodiments, the solvent is
ethyl acetate. In some embodiments, the temperature is about rt. In
some embodiments, the appropriate time is about 30 min to about 18
hours.
[0331] In some embodiments, II-4 is pre-treated with an
electrophile R.sup.6X in an appropriate solvent and at an
appropriate temperature. In some embodiments, the electrophile is
an alkyl halide. In some embodiments, X is chloro, bromo, or iodo.
In some embodiments, the electrophile is methyl iodide. In some
embodiments, the temperature is about -78.degree. C. In some
embodiments, the mixture is further reacted with a base for an
appropriate time and at an appropriate temperature to form an
alkylated product. In some embodiments, the base is lithium
diisopropyldiamide. In some embodiments, the appropriate time is
about 2 hours. In some embodiments, the temperature is about
-78.degree. C. In some embodiments, the mixture is further allowed
to warm to about rt over a suitable amount of time. In some
embodiments, a suitable amount of time is about overnight.
[0332] In some embodiments, ketone II-4 is transformed into
aldehyde II-7 as described in Scheme 1.
[0333] Alternatively in some embodiments, II-4 is reacted under
suitable one carbon-homologation conditions to provide alkene II-5.
In some embodiments, suitable one carbon-homologation conditions
include the use of phosphonium reagents. In some embodiments,
suitable one-carbon-homologation conditions, includes pre-treating
methyltriphenyl phosphonium bromide
[Ph.sub.3P.sup.+CH.sub.3Br.sup.-] with an appropriate base, in an
appropriate solvent for an appropriate amount of time at an
appropriate temperature before the addition of cyclohexanone II-4.
In some embodiments, the appropriate base is an organic base. In
some embodiments, the appropriate base is an alkoxide base. In some
embodiments, the appropriate base is potassium tert-butoxide. In
some embodiments, the appropriate solvent is toluene. In some
embodiments, the appropriate time before adding the ketone is about
30 min. In some embodiments, the temperature of the reaction before
adding the ketone is about 100.degree. C. In some embodiments,
ketone II-4 is added in the appropriate solvent, at the appropriate
temperature, and for the appropriate amount of time. In some
embodiments, the reaction temperature is about 50.degree. C. after
the addition of the ketone. In some embodiments, the ketone is
added in toluene. In some embodiments, the ketone is further
reacted at a suitable temperature for a suitable amount of time. In
some embodiments, the ketone is further reacted at about
100.degree. C. In some embodiments, the ketone is further reacted
for about 2 hours.
[0334] In some embodiments, alkene II-5 is subjected to hydration
conditions to form II-6. In some embodiments, the hydration
conditions include treatment with a reducing agent followed by an
oxidizing agent. The reducting agent is reacted with II-5 in the
appropriate solvent, at the appropriate temperature, and for the
appropriate amount of time. In some embodiments, the reducing agent
is a borane. In some embodiments, the reducing agent is
BH.sub.3--SMe.sub.2. In some embodiments, the reducing agent is
reacted with II-5 in THF. In some embodiments, the reaction
temperature is about 0.degree. C. In some embodiments, the reaction
proceeds for about one hour after addition of the reducing agent.
In some embodiments, the reaction further continues at about rt. In
some embodiments, the reaction further continues for about 3 hours.
In some embodiments, the intermediate borane product is further
oxidized with an oxiding agent to form alcohol II-6 in the
appropriate solvent, at the appropriate temperature, and for the
appropriate amount of time. In some embodiments, the oxidizing
agent is 30% H.sub.2O.sub.2. In some embodiments, the oxidation
reaction is carried out in the prescence of a base. In some
embodiments, the base is NaOH. In some embodiments, the solvent is
H.sub.2O. In some embodiments, the appropriate amount of time is
about overnight. In some embodiments, the appropriate temperature
is about rt.
[0335] In some embodiments, alcohol II-6 is subjected to an
oxidizing agent to form aldehyde II-7. In some embodiments, the
oxidizing agent is a Swern oxidant in the appropriate solvent, at
the appropriate temperature, and for the appropriate amount of
time. In some embodiments, the Swern oxidant is formed with DMSO
and oxalyl chloride. In some embodiments, the appropriate solvent
is dichloromethane. In some embodiments, the appropriate
temperature for Swern oxidant formation is about -78.degree. C. In
some embodiments, the appropriate time for Swern oxidant formation
is 30 min. In some embodiments, II-6 is reacted with the Swern
oxidant at about -78.degree. C. In some embodiments, II-6 is
reacted with the Swern oxidant for about one hour. In some
embodiments, a base is then added at the appropriate temperature
for the appropriate amount of time. In some embodiments, the base
is an amine base. In some embodiments, the amine base is
triethylamine. In some embodiments, the appropriate temperature is
about -78.degree. C. In some embodiments, the appropriate reaction
time after addition of the base is about one hour. In some
embodiments, oxidation produces II-7 as a mixture of cis and trans
isomers.
[0336] In some embodiments, the cis/trans mixture of II-7 is
equilibrated to mostly trans II-7 with an appropriate reagent, in
the appropriate solvent, at the appropriate temperature, and for
the appropriate time. In some embodiments, the appropriate reagent
is a base. In some embodiments, the base is an inorganic base. In
some embodiments, the base is sodium hydroxide. In some
embodiments, the appropriate solvent is a mixture, such as
H.sub.2O, EtOH and PhMe. In some embodiments, the appropriate time
is about 3 hours. In some embodiments, the appropriate temperature
is about rt. In some embodiments, further purification via
crystallization or chromatography provides pure trans aldehyde
II-7.
[0337] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
3
##STR00580##
[0338] In Scheme 3, substituents X.sup.2, X.sup.3 X.sup.4, R.sup.1,
R.sup.2, and m are as described herein. In some embodiments,
X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each X.sup.4 is C--H.
In some embodiments, R.sup.6 is alkyl. In some embodiments, R.sup.6
is methyl.
[0339] In some embodiments, ketone III-1 is treated with a base to
form an enolate with an appropriate base, in an appropriate
solvent, for an appropriate amount of time, at an appropriate
temperature. In some embodiments, the base is an organic base. In
some embodiments, the organic base is LiHMDS. In some embodiments,
enolate formation takes place at about -78.degree. C. In some
embodiments, the appropriate solvent is THF. In some embodiments,
the appropriate time is about one hour. In some embodiments, the
enolate of ketone III-1 is reacted with a suitable electrophile in
an appropriate solvent to form enol ether III-2 at the appropriate
temperature, for an appropriate amount of time. In some
embodiments, the electrophile forms a sulfate ester. In some
embodiments, the electrophile is PhNTf.sub.2. In some embodiments,
the appropriate temperature is about -78.degree. C. and the
appropriate time is about 2 hours. In some embodiments, the
reaction is further warmed to a suitable temperature over a
suitable period of time. In some embodiments, the suitable
temperature is about rt for about overnight.
[0340] In some embodiments, boronic acid III-3 is reacted with enol
triflate III-2 under suitable metal-catalyzed cross-coupling
reaction conditions to provide III-4. In some embodiments, suitable
metal-catalyzed cross-coupling conditions include palladium. In
some embodiments, suitable palladium-catalyzed cross-coupling
reaction conditions include Pd(dppf)Cl.sub.2 with an appropriate
base, with an appropriate solvent for an appropriate time and at an
appropriate temperature. In some embodiments, the base is an
inorganic base. In some embodiments, the inorganic base is a
carbonate base such as Na.sub.2CO.sub.3. In some embodiments, the
appropriate solvent is a dioxane/water mixture. In some
embodiments, the appropriate time and appropriate temperature is
about 6 hours at about 30.degree. C.
[0341] In some embodiments, III-4 is subjected under suitable
olefin reduction conditions followed by treatment under appropriate
acidic conditions to provide cyclohexanone III-5. In some
embodiments, suitable reduction conditions include
palladium-catalyzed hydrogenation conditions. In some embodiments,
palladium-catalyzed hydrogenation conditions include use of 10%
Pd/C with hydrogen (1 atm) in a suitable solvent, such as EtOAc,
for an appropriate amount of time at an appropriate temperature. In
some embodiments, the appropriate amount of time is about overnight
at about rt. In some embodiments, appropriate acidic conditions
include the use of formic acid in water and toluene for a suitable
amount of time at an appropriate temperature. In some embodiments,
the suitable amount of time at an appropriate temperature is about
overnight at about 120.degree. C.
[0342] In some embodiments, ketone III-5 is transformed into
aldehyde 1-6 or II-7, as shown in Scheme 1 and Scheme 2,
respectively.
[0343] In some embodiments, compounds described herein are prepared
as outlined in Scheme 4.
##STR00581##
[0344] In Scheme 4, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.8, R.sup.10 and R.sup.11
are as described herein. In some embodiments, X.sup.2 is
C--R.sup.2, X.sup.3 is C--H, and each X.sup.4 is C--H. In some
embodiments, X is a halide. In some embodiments, X is iodo or
bromo.
[0345] In some embodiments, trans aldehyde IV-1 is reacted with an
appropriate aniline IV-2 under suitable reductive amination
conditions. In some embodiments, suitable reductive amination
conditions include use of a suitable reducing agent and acetic acid
in an appropriate solvent, such as DCE or DCM, at an appropriate
temperature for a suitable amount of time. In some embodiments,
NaBH(OAc).sub.3 is used as a reducing agent. In some embodiments,
the appropriate temperature is about rt. In some embodiments, the
suitable amount of time is about one hour to about 2.5 hours. In
some embodiments, suitable reaction conditions include acetic acid
in an appropriate solvent, such as methanol, at an appropriate
temperature for a suitable amount of time before the addition of
the reducing agent. In some embodiments, the appropriate
temperature and time is about rt for about 5 minutes to about 4
hours. In some embodiments, the reaction is then further subjected
to a suitable reducing agent, such as NaBH.sub.3CN, for the
appropriate time and at the appropriate temperature. In some
embodiments, the appropriate amount of time is about overnight at
about rt.
[0346] In some embodiments, the acylation of amine IV-3 with an
acyl chloride affords compound IV-4. Suitable acylation conditions
include but are not limited to the use of a suitable base, such as
TEA or pyridine in a suitable solvent, such as DCM or toluene, for
an appropriate amount of time and at a suitable temperature, such
as about rt to about 80.degree. C. for about 1 hour to about
overnight. In some embodiments, pyridine is used as both the base
and the solvent. Other suitable conditions include the addition of
DMAP.
[0347] Boronic ester IV-5 may be prepared from IV-4 using
boron-halogen exchange conditions in some embodiments. Suitable
boron-halogen exchange conditions include but are not limited to
use of a suitable organometallic reagent and a suitable boron
reagent. In some embodiments, suitable organometallic reagents
include palladium. In some embodiments, suitable boron reagents
include bis(pinacolato)diboron. In some embodiments, suitable
palladium-catalyzed boron-halogen exchange conditions include
Pd(dppf)Cl.sub.2 with an appropriate base, in an appropriate
solvent for an appropriate time and at an appropriate temperature.
In some embodiments, the base is an inorganic base. In some
embodiments, the inorganic base is an acetate base such as KOAc. In
some embodiments, the appropriate solvent is toluene. In some
embodiments, the appropriate time and appropriate temperature is
about 4 hours to about overnight and about 100.degree. C. to about
115.degree. C.
[0348] In some embodiments, boronic ester IV-5 is reacted with an
aromatic halide under suitable metal-catalyzed cross-coupling
reaction conditions to provide IV-6. In some embodiments, the
aromatic halide is an aromatic bromide or iodide. In some
embodiments, suitable metal-catalyzed cross-coupling conditions
include use of palladium. In some embodiments, suitable
palladium-catalyzed cross-coupling reaction conditions include
Pd(dppf)Cl.sub.2, Pd(PPh.sub.3).sub.4, or chloro
[(di(1-adamaniyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)
with an appropriate base, in an appropriate solvent for an
appropriate time and at an appropriate temperature. In some
embodiments, the base is an inorganic base. In some embodiments,
the inorganic base is a carbonate base such as K.sub.2CO.sub.3,
Na.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. In some embodiments, the
inorganic base is K.sub.3PO.sub.4. In some embodiments, the
appropriate solvent is a dioxane/water, or DMF/water mixture. In
some embodiments, the appropriate solvent is EtOH or dioxane. In
some embodiments, the appropriate time and appropriate temperature
is about 10 min to about 4 hours at about 50.degree. C. to about
80.degree. C. In some embodiments, the appropriate time and
appropriate temperature is about 0.5 hours to about 6 hours at
about 80.degree. C. In some embodiments, the appropriate time and
appropriate temperature is about 15 mins to about 3.5 hours at
about 80.degree. C. In some embodiments, the appropriate time and
appropriate temperature is about 15 hours at about 90.degree. C. In
some embodiments, the appropriate time and appropriate temperature
is about one hour at about 50.degree. C. In some embodiments, the
appropriate time and appropriate temperature is about 3 hours at
about 80.degree. C. to about 100.degree. C.
[0349] In some embodiments, boronic ester IV-5 is reacted with a
nitrogen-containing heterocycle under suitable metal-catalyzed
cross-coupling reaction conditions to provide IV-6. In some
embodiments, suitable metal-catalyzed cross-coupling conditions
include use of copper. In some embodiments, suitable
copper-catalyzed cross-coupling reaction conditions include
Cu(OAc).sub.2 with an appropriate ligand, an appropriate oxidant,
in an appropriate solvent for an appropriate time and at an
appropriate temperature. In some embodiments, an appropriate ligand
is N,N,N',N'-tetramethylethylenediamine. In some embodiments, an
appropriate oxidant is O.sub.2. An appropriate solvent is a water
and methanol mixture. In some embodiments, the appropriate time and
appropriate temperature is about overnight at about rt.
[0350] In some embodiments, aryl halide IV-4 is reacted with a
boron reagent under suitable metal-catalyzed cross-coupling
reaction conditions to provide IV-6. In some embodiments, the boron
reagent is an aromatic boronic acid. In some embodiments, the boron
reagent is an aromatic boronic ester. In some embodiments, the
boron reagent is an aromatic pinacolyl boronic ester. In some
embodiments, suitable metal-catalyzed cross-coupling conditions
include palladium. In some embodiments, suitable
palladium-catalyzed cross-coupling reaction conditions include
Pd(dppf)Cl.sub.2 or Pd(PPh.sub.3).sub.4 with an appropriate base,
with an appropriate solvent for an appropriate time and at an
appropriate temperature. In some embodiments, the base is an
inorganic base. In some embodiments, the inorganic base is a
carbonate base such as Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3, or
K.sub.2CO.sub.3. In some embodiments, the appropriate solvent is a
DMF/water mixture. In some embodiments, the appropriate solvent is
a dioxane/water mixture. In some embodiments, the appropriate time
and appropriate temperature is about 10 min to about 2 hours at
about 50.degree. C. to about 100.degree. C. In some embodiments,
the appropriate time and appropriate temperature is about 15 min to
about 30 min at about 80.degree. C.
[0351] In some embodiments, compound IV-6 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide
IV-4 with a nitrogen-containing heterocycle. In some embodiments,
halide IV-4 is an iodide. In some embodiments, metal-catalyzed
cross couplings include Buchwald-Hartwig palladium-catalyzed
amination conditions. Suitable palladium catalysts for
cross-coupling include but are not limited to Pd.sub.2(dba).sub.3
with a suitable ligand in a suitable solvent, such as dioxane, with
an appropriate base at a suitable temperature for an appropriate
amount of time. In some embodiments, the suitable ligand is a
phosphine ligand. In some embodiments, a suitable phosphine is
2-(di-tert-butylphosphino)biphenyl. butylphosphino)biphenyl. In
some embodiments, the appropriate base is an organic base. In some
embodiments, a suitable organic base is sodium tert-butoxide. In
some embodiments, the suitable temperature is 80.degree. C. In some
embodiments, the appropriate amount of time is about overnight.
[0352] In some embodiments, compound IV-6 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide
IV-4 with a tin reagent. In some embodiments, halide IV-4 is a
bromide. In some embodiments, the tin reagent is an aromatic tin
reagent. In some embodiments, metal-catalyzed cross couplings
include Stille palladium-catalyzed cross-coupling conditions.
Suitable palladium catalysts for cross-coupling include but are not
limited to Pd(PPh.sub.3).sub.4 in a suitable solvent, such as DMF
or dioxane, at a suitable temperature for an appropriate amount of
time. In some embodiments, the suitable temperature is 90.degree.
C. In some embodiments, the appropriate amount of time is about 2
hours. In some embodiments, the suitable temperature is 100.degree.
C. In some embodiments, the appropriate amount of time is about 4
hours.
[0353] In some embodiments, compound IV-6 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide
IV-4 with an aromatic compound. In some embodiments, halide IV-4 is
a bromide. In some embodiments, metal-catalyzed cross couplings
include C--H activation cross-coupling conditions. In some
embodiments, C--H activation cross-coupling conditions include use
of palladium catalysts. Suitable palladium catalysts for
cross-coupling include but are not limited to Pd(OAc).sub.2 with a
suitable ligand in a suitable solvent, such as dioxane, with an
appropriate base at a suitable temperature for an appropriate
amount of time. In some embodiments, the suitable ligand is a
phosphine ligand. In some embodiments, a suitable phosphine is
(2-biphenyl)dicyclohexylphosphine. In some embodiments, the
appropriate base is an inorganic base. In some embodiments, a
suitable inorganic base is K.sub.2CO.sub.3. In some embodiments,
the suitable temperature is 110.degree. C. In some embodiments, the
appropriate amount of time is about overnight.
[0354] In some embodiments, R.sup.10 or R.sup.11 is a protected
alcohol. In some embodiments, R.sup.10 or R.sup.11 is an alcohol
protected with a silyl ether. In some embodiments, protecting
groups are removed to produce a free alcohol using suitable
deprotection conditions including appropriate solvent, temperature
and time to produce IV-6. In some embodiments, suitable
deprotection conditions include the use of aqueous HCl. In some
embodiments, the appropriate solvent is water, THF, methanol, or a
combination of solvents. In some embodiments, the appropriate time
at the appropriate temperature is about 1 hour at about 0.degree.
C. to about rt.
[0355] In some embodiments, compounds described herein are prepared
as outlined in Scheme 5.
##STR00582##
[0356] In Scheme 5, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, R.sup.10, R.sup.11, and m are as described herein. In some
embodiments, X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each
X.sup.4 is C--H. In some embodiments, X is a halide. In some
embodiments, X is iodo or bromo. In some embodiments, X is
hydrogen. In some embodiments, M is a metal or metalloid-containing
substituent. In some embodiments, metal or metalloids include
boron, tin, or zinc.
[0357] In some embodiments, boron reagent V-1 is reacted with an
aromatic halide V-7 under suitable metal-catalyzed cross-coupling
reaction conditions to provide V-2. In some embodiments, the
aromatic halide is an aromatic bromide or aromatic iodide. In some
embodiments, suitable metal-catalyzed cross-coupling conditions
include palladium. In some embodiments, suitable
palladium-catalyzed cross-coupling reaction conditions include
Pd(dppf)Cl.sub.2 with an appropriate base, with an appropriate
solvent for an appropriate time and at an appropriate temperature.
In some embodiments, the base is an inorganic base. In some
embodiments, the inorganic base is a carbonate base such as
Na.sub.2CO.sub.3. In some embodiments, the appropriate solvent is a
mixture of dioxane, ethanol and water. In some embodiments, the
appropriate time and appropriate temperature is about about
overnight at about 80.degree. C.
[0358] In some embodiments, compound V-2 is prepared from
appropriate metal-catalyzed cross coupling conditions of an
aromatic halide V-1 with a boron reagent V-7. In some embodiments,
appropriate metal-catalyzed cross coupling conditions, such as
Suzuki cross-coupling conditions, are described in Schemes 4 and
5.
[0359] In some embodiments, compound V-2 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide V-1
with a nitrogen-containing heterocycle V-7. In some embodiments,
appropriate metal-catalyzed cross coupling conditions, such as
Buchwald-Hartwig amination conditions, are described in Scheme
4.
[0360] In some embodiments, compound V-2 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide V-1
with a tin reagent V-7. In some embodiments, appropriate
metal-catalyzed cross coupling conditions, such as Stille
cross-coupling conditions, are described in Scheme 4.
[0361] In some embodiments, compound V-2 is prepared from
appropriate metal-catalyzed cross coupling conditions of tin
reagent V-1 with an aromatic halide V-7. In some embodiments,
appropriate metal-catalyzed cross coupling conditions, such as
Stille cross-coupling conditions, are described in Scheme 4.
[0362] In some embodiments, compound V-2 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide V-1
with an aromatic compound V-7. In some embodiments, appropriate
metal-catalyzed cross coupling conditions, such as C--H activation
conditions, are described in Scheme 4.
[0363] In some embodiments, boron reagent V-3 is reacted with an
aromatic halide V-8 under suitable metal-catalyzed cross-coupling
reaction conditions to provide V-4. In some embodiments, boron
reagent V-3 is a boronic acid or boronic ester. In some
embodiments, the aromatic halide is aromatic bromide or aromatic
iodide. In some embodiments, suitable metal-catalyzed
cross-coupling conditions include palladium. In some embodiments,
suitable palladium-catalyzed cross-coupling reaction conditions
include Pd(dppf)Cl.sub.2 with an appropriate base, with an
appropriate solvent for an appropriate time and at an appropriate
temperature. In some embodiments, the base is an inorganic base. In
some embodiments, the inorganic base is a carbonate base such as
K.sub.2CO.sub.3. In some embodiments, the appropriate solvent is a
dioxane. In some embodiments, the appropriate time and appropriate
temperature is about about 4 hours at about 80.degree. C.
[0364] In some embodiments, aryl halide V-3 is reacted with boron
reagent V-8 under suitable metal-catalyzed cross-coupling reaction
conditions to provide V-4. In some embodiments, the boron reagent
is an aromatic boronic acid. In some embodiments, the boron reagent
is an aromatic boronic ester. In some embodiments, the aryl halide
is an aryl iodide or aryl bromide. In some embodiments, suitable
metal-catalyzed cross-coupling conditions include palladium. In
some embodiments, suitable palladium-catalyzed cross-coupling
reaction conditions include Pd(dppf)Cl.sub.2 with an appropriate
base, with an appropriate solvent for an appropriate time and at an
appropriate temperature. In some embodiments, the base is an
inorganic base. In some embodiments, the inorganic base is a
carbonate base such as K.sub.2CO.sub.3. In some embodiments, the
appropriate solvent is dioxane. In some embodiments, the
appropriate time and appropriate temperature is about about 20 min
at about 90.degree. C.
[0365] In some embodiments, compound V-4 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide V-3
with nitrogen-containing heterocycle V-8. In some embodiments,
appropriate metal-catalyzed cross coupling conditions, such as
Buchwald-Hartwig amination conditions, are described in Scheme
4.
[0366] In some embodiments, compound V-4 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide V-3
with a tin reagent V-8. In some embodiments, appropriate
metal-catalyzed cross coupling conditions, such as Stille
cross-coupling conditions, are described in Scheme 4.
[0367] In some embodiments, compound V-4 is prepared from
appropriate metal-catalyzed cross coupling conditions of tin
reagent V-3 with an aromatic halide V-8. In some embodiments,
appropriate metal-catalyzed cross coupling conditions, such as
Stille cross-coupling conditions, are described in Scheme 4.
[0368] In some embodiments, compound V-4 is prepared from
appropriate metal-catalyzed cross coupling conditions of halide V-3
with an aromatic compound V-8. In some embodiments, appropriate
metal-catalyzed cross coupling conditions, such as C--H activation
conditions, are described in Scheme 4.
[0369] In some embodiments, V-2 is subjected to suitable nitro
reduction conditions to provide aniline V-4. Suitable nitro
reduction conditions include the use of metal catalysts. Suitable
metal-catalyzed reductions include palladium-catalyzed
hydrogenation conditions. In some embodiments, suitable
palladium-catalyzed hydrogenation conditions include use of 10%
Pd/C with hydrogen (1 atm) in a suitable solvent, such as methanol,
for an appropriate amount of time at an appropriate temperature. In
some embodiments, appropriate conditions include addition of HCl in
water. In some embodiments, the appropriate amount of time at the
appropriate temperature is about one hour at about rt.
[0370] Alternatively in some embodiments, suitable nitro reduction
conditions include use of a tin reducing agent in the appropriate
solvent, for the appropriate amount of time at the appropriate
temperature. In some embodiments, suitable tin reducing agents
include SnCl.sub.2--H.sub.2O. In some embodiments, the appropriate
solvent is a water and ethanol mixture. In some embodiments, the
appropriate amount of time at the appropriate temperature is about
two hours to about 16 hours at about 80.degree. C. In some
embodiments, the appropriate amount of time at the appropriate
temperature is about two hours to about 2 hours at about rt.
[0371] Alternatively in some embodiments, suitable nitro reduction
conditions include use of a zinc reducing agent and an acid in the
appropriate solvent, for the appropriate amount of time at the
appropriate temperature. In some embodiments, the appropriate acid
includes acetic acid. In some embodiments, suitable zinc reducing
agents include metallic Zn. In some embodiments, the appropriate
solvent is ACN. In some embodiments, the appropriate amount of time
at the appropriate temperature is about one hour at about 0.degree.
C. to about rt.
[0372] In some embodiments, an appropriate aldehyde is reacted with
aniline V-4 under suitable reductive amination conditions to obtain
V-5. In some embodiments, suitable reductive amination conditions
include use of a suitable reducing agent in an appropriate solvent,
at an appropriate temperature for a suitable amount of time. In
some embodiments, an appropriate solvent is DCE or DCM. In some
embodiments, an appropriate solvent is DCE/acetic acid or
DCM/acetic acid mixtures. In some embodiments, NaBH(OAc).sub.3 is
used as a reducing agent. In some embodiments, the appropriate
temperature is about 0.degree. C. to about rt. In some embodiments,
the suitable amount of time is about one hour to about overnight.
In some embodiments, suitable reaction conditions include acetic
acid in an appropriate solvent, such as methanol, at an appropriate
temperature for a suitable amount of time before addition of a
reducing agent. In some embodiments, the appropriate temperature
and time is about rt for about 5 minutes to about 4 hours. In some
embodiments, the reaction is subjected to a suitable reducing
agent, such as NaBH.sub.3CN, for the appropriate time and at the
appropriate temperature. In some embodiments, the appropriate
amount of time at the appropriate temperature after addition of
NaBH.sub.3CN is about overnight at about rt.
[0373] In some embodiments, the acylation of amine V-5 with an acyl
chloride affords compound V-6. Suitable acylation conditions
include but are not limited to the use of a suitable base, such as
TEA or pyridine in a suitable solvent, such as DCM, toluene or
pyridine, for an appropriate amount of time and at a suitable
temperature after addition of the acyl chloride. In some
embodiments, a suitable temperature and appropriate amount of time
are about rt to about 80.degree. C. for about one hour to about
overnight. Other suitable conditions include the addition of DMAP.
In some embodiments, the acyl chloride is added in an appropriate
solvent, such as toluene. In some embodiments, a suitable
temperature and appropriate amount of time after addition of the
acid chloride are about 0.degree. C. to about 50.degree. C. or
about 0.degree. C. to about 80.degree. C. for about 10 min to about
overnight.
[0374] In some embodiments, R.sup.10 or R.sup.11 is a protected
alcohol. In some embodiments, R.sup.10 or R.sup.11 is an alcohol
protected with a silyl ether. In some embodiments, protecting
groups are removed to produce a free alcohol using suitable
deprotection conditions as described in Scheme 4.
[0375] In some embodiments, compounds described herein are prepared
as outlined in Scheme 6.
##STR00583##
[0376] In Scheme 6, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, R.sup.12, and m are as described herein. In some
embodiments, X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each
X.sup.4 is C--H.
[0377] In some embodiments, compound VI-2 is prepared from the
O-alkylation of VI-1 with R.sup.12X, a suitable base, and suitable
solvent, such as THF, at a suitable temperature for a suitable
amount of time. In some embodiments, X is a halide. In some
embodiments, a suitable base is NaH. In some embodiments, the
compound VI-1 is pretreated with the suitable base for an
appropriate amount of time at an appropriate temperature, such as
about 0.5 h at about 0.degree. C., before the addition of the
halide R.sup.12X. In some embodiments, the appropriate time and
temperature is about overnight at about 60.degree. C.
[0378] In some embodiments, compounds described herein are prepared
as outlined in Scheme 7. .sub.and
##STR00584##
[0379] In Scheme 7, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, and m are as described herein. In some embodiments,
X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each X.sup.4 is C--H.
In some embodiments, each R is independently alkyl, heteroalkyl, or
hydroxyalkyl or hydrogen, or both R are taken together to form a
substituted or unsubstituted fused 4-, 5-, or 6-membered ring with
0-3 N atoms and 0-2 O or S atoms in the ring.
[0380] In some embodiments, VII-2 is prepared from VII-1 and an
amine NHR.sub.2. In some embodiments, VII-1 is subjected to
carbonyldiimidazole in an appropriate solvent, such as ACN, at a
suitable temperature, such as at about 80.degree. C., for an
appropriate amount of time to provide the intermediate carbamoyl
imidazole. In some embodiments, the appropriate amount of time is
about 2 hours to about 6 hours or about overnight. In some
embodiments, the intermediate carbamoyl imidazole is treated with
NHR.sub.2 in a suitable solvent, and the reaction is allowed to
proceed for an appropriate amount of time at an appropriate
temperature. In some embodiments, the suitable solvent is
acetonitrile. In some embodiments, the suitable solvent is MeOH,
THF, or DCM. In some embodiments, the NHR.sub.2 is added as a
solution in MeOH, THF, or DCM. In some embodiments, the NHR.sub.2
is added neat. In some embodiments, the appropriate amount of time
at the appropriate temperature is about 15 minutes to about
overnight at about rt. In some embodiments, the appropriate amount
of time is about 1 day to about 7 days. In some embodiments, the
appropriate temperature is about rt to about 50.degree. C. or about
rt to about 100.degree. C. In some embodiments, when an NHR.sub.2
hydrochloride is used instead of NHR.sub.2, then a suitable base,
such as iPr.sub.2NEt, is added prior to addition of the NHR.sub.2
hydrochloride.
[0381] In some embodiments, compounds described herein are prepared
as outlined in Scheme 8.
##STR00585##
[0382] In Scheme 8, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.8, and m are as described herein. In some
embodiments, X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each
X.sup.4 is C--H. In some embodiments, each R is independently
alkyl, heteroalky, hydroxyalkyl or hydrogen, or both R are taken
together to form a substituted or unsubstituted fused 4-, 5-, or
6-membered ring with 0-3 N atoms and 0-2 O or S atoms in the
ring.
[0383] In some embodiments, VIII-2 is prepared from VIII-1 and an
amine NHR.sub.2 via an acid. In some embodiments, VIII-1 is
subjected to hydrolysis conditions to form an intermediate acid, in
an appropriate solvent, at a suitable temperature, for a suitable
period of time. In some embodiments, the hydrolysis conditions are
basic. In some embodiments, the hydrolysis conditions include the
use of NaOH or LiOH. In some embodiments, the solvent is a
THF/methanol/water mixture or a THF/water mixture. In some
embodiments, a suitable temperature is about rt, and a suitable
time is about 2 hours to about overnight. In some embodiments, the
intermediate hydrolysis product is the desired compound. In some
embodiments, the intermediate hydrolysis product and an amine
NHR.sub.2 are reacted under amidation conditions to form VIII-2. In
some embodiments, a coupling agent, such as HATU is added to the
acid in the presence of a base for a suitable period of time, at a
suitable temperature, and in a suitable solvent. In some
embodiments, the base is an amine base, such as
N,N-diisopropylethylamine. In some embodiments, the solvent is DMF.
In some embodiments, after an appropriate amount of time at a
suitable temperature, such as about 10 minutes at about 0.degree.
C., NHR.sub.2 is added and the reaction is allowed to proceed for
an appropriate amount of time at an appropriate temperature to form
VIII-2. In some embodiments, DBU is also added. In some
embodiments, the appropriate amount of time at the appropriate
temperature is about 10 minutes to about 30 minutes at about
0.degree. C. to about rt.
[0384] In some embodiments, the intermediate hydrolysis product is
treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (EDC), Et.sub.3N, DMAP, and HOBt at a suitable
temperature in a suitable solvent. In some embodiments, the
suitable solvent is DCM. In some embodiments, the suitable
temperature is 0.degree. C. In some embodiments, after a suitable
period of time, such as about 10 minutes, NHR.sub.2 is added, and
the reaction is allowed to proceed for an appropriate amount of
time at an appropriate temperature to form VIII-2. In some
embodiments, the appropriate amount of time at the appropriate
temperature is about overnight at about 0.degree. C. to about
rt.
[0385] In some embodiments, compounds described herein are prepared
as outlined in Scheme 9.
##STR00586##
[0386] In Scheme 9, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, R.sup.14, and m are as described herein. In some
embodiments, X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each
X.sup.4 is C--H.
[0387] In some embodiments, IX-1 is subjected under appropriate
acidic conditions to provide an amine. In some embodiments, the
appropriate acidic conditions include the use of TFA in a suitable
solvent, such as DCM, at an appropriate temperature for an
appropriate amount of time. In some embodiments, the appropriate
acidic conditions include the use of HCl in a suitable solvent,
such as dioxane, at an appropriate temperature for an appropriate
amount of time. In some embodiments, the appropriate temperature
for an appropriate amount of time is about 0.degree. C. to about rt
for about 0.5 hours to about 2 hours. In some embodiments, the
amine is reacted with an anhydride (R.sup.14CO).sub.2O to provide
IX-2 in the presence of a suitable base and solvent at an
appropriate temperature for an appropriate amount of time. In some
embodiments, the suitable base is TEA or pyridine. In some
embodiments, the suitable solvent is ethyl acetate or DCM. In some
embodiments, the appropriate temperature for an appropriate amount
of time is about 0.degree. C. to about rt for about 10 minutes to
about 2 hours. Alternatively, the amine is reacted with acyl
chloride R.sup.14COCl or chloroformate ClCO.sub.2R.sup.14 to
provide IX-2 in the presence of a suitable base and solvent at an
appropriate temperature for an appropriate amount of time. In some
embodiments, the suitable base is pyridine or TEA. In some
embodiments, the suitable solvent is DCM or ethyl acetate. In some
embodiments, the appropriate temperature for an appropriate amount
of time is about 0.degree. C. to about rt for about 10 minutes to
about 2 hours. Alternatively, the amine is reacted with sulfonyl
chloride R.sup.14SO.sub.2Cl to provide IX-2 in the presence of a
suitable base and solvent at an appropriate temperature for an
appropriate amount of time. In some embodiments, the suitable base
is TEA or pyridine. In some embodiments, the suitable solvent is
DCM or ethyl acetate. In some embodiments, the appropriate
temperature for an appropriate amount of time is about 0.degree. C.
for about 10 min to about 2 hours. Alternatively, the amine is
reacted with carboxylic acid R.sup.14CO.sub.2H to provide IX-2 in
the presence of a suitable base and solvent for an appropriate
amount of time. In some embodiments, the suitable base is TEA. In
some embodiments, the suitable solvent is DMF. In some embodiments,
the appropriate temperature is about 0.degree. C. In some
embodiments, propylphosphonic anhydride is added after an
appropriate amount of time, and the reaction is allowed to proceed
at an appropriate temperature for an appropriate amount of time. In
some embodiments, the appropriate temperature for an appropriate
amount of time is about 0.degree. C. to about rt for about
overnight.
[0388] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
10.
##STR00587##
[0389] In Scheme 10, substituents X.sup.2, X.sup.3, X.sup.4,
R.sup.1, and R.sup.2 are as described herein. In some embodiments,
X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each X.sup.4 is C--H.
In some embodiments, X is a halide. In some embodiments, X is
chloro, bromo or iodo.
[0390] In some embodiments, halide X-1 is cooled to a suitable
temperature, reacted under suitable metal-halogen exchange
conditions with an appropriate solvent for an appropriate time and
at an appropriate temperature, and then later reacted with an
appropriate ketone X-2 for an appropriate time and at an
appropriate temperature to provide a tertiary alcohol. In some
embodiments, suitable metal-halogen exchange conditions include an
organometallic reagent. In some embodiments, an appropriate solvent
is THF. In some embodiments, the organometallic reagent is an alkyl
lithium. In some embodiments, the alkylithium is n-butyl lithium.
In some embodiments, X-1 is cooled to about -78.degree. C. before
addition of an organometallic reagent. In some embodiments, X-1 is
reacted for about one hour at about -78.degree. C. before addition
of the appropriate ketone X-2. In some embodiments, X-1 is reacted
for about 2 hours after the addition of ketone X-2. In some
embodiments, the appropriate temperature for reacting X-1 and
ketone X-2 is about -78.degree. C. In some embodiments, the
tertiary alcohol is reacted under appropriate allylation conditions
which include use of an allylating reagent and a Lewis acid, in an
appropriate solvent for an appropriate time and at an appropriate
temperature to form X-3. In some embodiments, the appropriate
allylating reagent is allyltrimethylsilane. In some embodiments,
the appropriate Lewis acid is BF.sub.3--OEt.sub.2. In some
embodiments, the appropriate solvent is DCM. In some embodiments,
the appropriate temperature for the appropriate time is about
-78.degree. C. for about 1 hour. In some embodiments, the reaction
is further warmed to about rt for about overnight. In some
embodiments, the appropriate temperature for the appropriate time
is about 0.degree. C. for about overnight.
[0391] In some embodiments, X-3 is reacted under suitable oxidative
cleavage conditions for the appropriate time period, in the
appropriate solvent, and at the appropriate temperature to produce
X-4. In some embodiments, oxidative cleavage conditions include the
use of an osmium reagent and N-methylmorpholine N-oxide to form an
intermediate diol. In some embodiments, the osmium reagent is
OsO.sub.4 or K.sub.2OsO.sub.4-2H.sub.2O. In some embodiments, an
appropriate solvent is an ACN/water mixture. In some embodiments,
an appropriate temperature for the appropriate time is about
0.degree. C. to about rt for about overnight. In some embodiments,
the diol is cleaved to form X-4 under the appropriate oxidative
cleavage conditions for the appropriate time period, in the
appropriate solvent, and at the appropriate temperature. In some
embodiments, appropriate oxidative cleavage conditions include the
use of NaIO.sub.4. In some embodiments, an appropriate solvent is a
THF/water mixture. In some embodiments, the appropriate temperature
for the appropriate time is is about 0.degree. C. to about rt for
about overnight.
[0392] In some embodiments, X-4 is reduced to a primary alcohol
under suitable reducing conditions, and then halogenated under
suitable halogenation conditions to produce X-5. In some
embodiments, suitable reducing conditions include the use of a
borohydride reagent. In some embodiments, reducing conditions
include the use of NaBH.sub.4 in the appropriate solvent, at an
appropriate temperature for the appropriate amount of time. In some
embodiments, an appropriate solvent is THF. In some embodiments, an
appropriate temperature for the appropriate time is about 0.degree.
C. for about one hour. In some embodiments, the reaction is warmed
to about rt for about overnight. The alcohol is reacted under
suitable halogenation conditions to produce an alkyl halide in some
embodiments. In some embodiments, suitable halogenation conditions
are bromination conditions that include use of CBr.sub.4 in an
appropriate solvent at an appropriate initial temperature followed
by PPh.sub.3 in the appropriate solvent, at an appropriate
temperature for an appropriate time. In some embodiments, the
appropriate solvent is a halogenated solvent, such as DCM. In some
embodiments, an appropriate initial temperature is about 0.degree.
C. In some embodiments, an appropriate temperature and time after
addition of PPh.sub.3 is about 0.degree. C. for about 1 hour. In
some embodiments, an appropriate solvent for addition of PPh.sub.3
is THF. In some embodiments, the reaction is further warmed to
about rt for about overnight.
[0393] In some embodiments, X-5 is subjected to intramolecular
alkylation conditions to form X-6. In some embodiments,
intramolecular alkylation conditions include a suitable base. In
some embodiments, the suitable base is lithium diisopropylamide in
the appropriate solvent, at an appropriate temperature for an
appropriate amount of time. In some embodiments, the appropriate
solvent is a HMPA and THF mixture. In some embodiments, the
appropriate temperature for the appropriate amount of time is about
-78.degree. C. for about 3 hours or about -78.degree. C. to rt for
about overnight.
[0394] Ester X-6 is reduced to an alcohol by suitable reduction
conditions followed by oxidation to aldehyde X-7 by suitable
oxidation conditions in some embodiments. In some embodiments,
suitable reduction conditions include the use of DIBALH in an
appropriate solvent at an appropriate temperature for an
appropriate time. In some embodiments, the appropriate solvent is
DCM. In some embodiments, the appropriate temperature for the
appropriate time is about -78.degree. C. for about one hour. In
some embodiments, the reaction is further warmed to about rt for
about two hours to produce an alcohol. In some embodiments,
suitable oxidation conditions are chromium-based oxidations. In
some embodiments, suitable oxidation conditions include the use of
PCC in an appropriate solvent at an appropriate temperature for an
appropriate time. In some embodiments, silica gel is added. In some
embodiments, the appropriate solvent is DCM. In some embodiments,
the appropriate temperature is about rt for about 2 hours.
Alternatively in some embodiments, the oxidations conditions
include the use of oxalyl chloride and DMSO with an amine base in
an appropriate solvent at an appropriate temperature for an
appropriate time. In some embodiments, the appropriate amine base
is TEA. In some embodiments, the appropriate solvent is DCM. In
some embodiments, the appropriate temperature for the appropriate
amount of time is about -78.degree. C. for about 1 hour.
[0395] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
11.
##STR00588##
[0396] In some embodiments, XI-1 is subjected to alcohol protection
conditions to form a bis-silyl intermediate, followed by hydrolysis
conditions to form XI-2. In some embodiments, the alcohol
protection conditions include the use of TBSC1 and an appropriate
base at the appropriate temperature, in the appropriate solvent,
and for an appropriate period of time. In some embodiments, the
appropriate solvent is DMF. In some embodiments, the appropriate
base is imidazole. In some embodiments, the appropriate temperature
for the appropriate time is about rt for about 2 hours. In some
embodiments, the intermediate silyl ester is subjected to
hydrolysis conditions to form XI-2. In some embodiments, hydrolysis
conditions include treatment with a base, at an appropriate
temperature, in an appropriate solvent, and for an appropriate
period of time. In some embodiments, the appropriate solvent is an
EtOH, H.sub.2O, THF mixture. In some embodiments, the appropriate
base is K.sub.2CO.sub.3. In some embodiments, the appropriate
temperature for the appropriate time is about rt for about 3
hours.
[0397] Compound XI-2 is converted to acid chloride XI-3, in some
embodiments, under chlorinating conditions. In some embodiments,
chlorinating conditions include the use of
(chloromethylene)dimethyliminium chloride and a base at a suitable
temperature, in a suitable solvent. In some embodiments, the
suitable base is anhydrous K.sub.2CO.sub.3. In some embodiments,
the suitable temperature is about 0.degree. C. In some embodiments,
a suitable solvent is toluene. In some embodiments, XI-2 is added
and the mixture stirred at a suitable temperature for a suitable
time to produce XI-3. In some embodiments, the suitable temperature
for the suitable time is about rt for about 0.5 to about one
hour.
[0398] In some embodiments, compounds described herein are prepared
as outlined in Scheme 12.
##STR00589##
[0399] In Scheme 12, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.6, R.sup.8, R.sup.10,
R.sup.11, and m are as described herein. In some embodiments,
X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each X.sup.4 is
C--H.
[0400] Alcohol XII-1 is reacted under suitable halogenation
conditions to produce an alkyl halide XII-2 in some embodiments. In
some embodiments, suitable halogenation conditions are bromination
conditions including the use of CBr.sub.4 in an appropriate solvent
at an appropriate initial temperature followed by PPh.sub.3 in the
appropriate solvent, at an appropriate temperature for an
appropriate time. In some embodiments, the appropriate solvent is a
halogenated solvent, such as DCM. In some embodiments, an
appropriate initial temperature is about 0.degree. C. In some
embodiments, an appropriate temperature and time after addition of
PPh.sub.3 is about 0.degree. C. for about one hour. In some
embodiments, the reaction is further warmed to about rt for about
overnight.
[0401] In some embodiments, the acylation of amine XII-3 with an
acyl chloride affords compound XII-4. Suitable acylation conditions
include but are not limited to the use of a suitable base, such as
pyridine in a suitable solvent, such as DCM or toluene at a
suitable temperature, such as about 0.degree. C. In some
embodiments, an acyl chloride is added in an appropriate solvent at
an appropriate temperature for an appropriate amount of time. In
some embodiments, the appropriate solvent is toluene. In some
embodiments, the appropriate temperature is about 0.degree. C. then
warming to rt for about overnight.
[0402] In some embodiments, compound XII-5 is prepared from the
N-alkylation of XII-4 with bromide XII-2 and a suitable base in
suitable solvent, such as DMF, at a suitable temperature for a
suitable amount of time. Suitable bases include NaH. In some
embodiments, the compound XII-4 is pretreated with the suitable
base for an appropriate amount of time at an appropriate
temperature, such as about two hours at about 0.degree. C. to about
rt, before the addition of bromide XII-2. In some embodiments, the
appropriate time and temperature after addition of bromide XII-2 is
about rt for about overnight. In some embodiments, R.sup.10 or
R.sup.11 is a protected alcohol. In some embodiments, R.sup.10 or
R.sup.11 is an alcohol protected with a silyl ether. In some
embodiments, protecting groups are removed to produce a free
alcohol using suitable deprotection conditions including an
appropriate solvent, temperature and time to produce XII-5. In some
embodiments, suitable deprotection conditions include the use of
fluoride reagents. In some embodiments, the fluoride reagent is
NH.sub.4F. In some embodiments, the appropriate solvent is
methanol. In some embodiments, the appropriate time at the
appropriate temperature is about overnight at about 60.degree.
C.
[0403] In some embodiments, compounds described herein are prepared
as outlined in Scheme 13.
##STR00590##
[0404] In Scheme 13, ring A and substituents X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, R.sup.10, R.sup.11, and m are as described herein. In some
embodiments, X.sup.2 is C--R.sup.2, X.sup.3 is C--H, and each
X.sup.4 is C--H. In some embodiments, X is a suitable
cross-coupling substituent. In some embodiments, X is a halide. In
some embodiments, X is chloro, bromo, or iodo.
[0405] In some embodiments, compound XIII-1 is reacted with a
suitable acetylene source under suitable metal-catalyzed
cross-coupling reaction conditions to provide XIII-2 In some
embodiments, suitable metal-catalyzed cross-coupling conditions
include palladium. In some embodiments, a suitable acetylene source
is trimethylsilylacetylene. In some embodiments, suitable
palladium-catalyzed cross-coupling reaction conditions include
Pd(PPh.sub.3).sub.2Cl.sub.2, a copper catalyst, with an appropriate
base, for an appropriate time and at an appropriate temperature. In
some embodiments, the copper catalyst is CuI. In some embodiments,
the base is an amine base, such as TEA. In some embodiments, the
appropriate time and appropriate temperature is about 6 hours at
about 90.degree. C. In some embodiments, the TMS-group is removed
after the cross-coupling, under suitable deprotection conditions
including an appropriate solvent, temperature and time to produce
to form XIII-2. In some embodiments, suitable deprotection
conditions include the use of fluoride reagents. In some
embodiments, the fluoride reagent is NH.sub.4F. In some
embodiments, the appropriate solvent is methanol. In some
embodiments, the appropriate time is about one hour at about
60.degree. C.
[0406] In some embodiments, acetylene XIII-2 is reacted with a
suitable aromatic halide under suitable metal-catalyzed
cross-coupling reaction conditions to provide XIII-3 In some
embodiments, suitable metal-catalyzed cross-coupling conditions
include palladium. In some embodiments, the aromatic halide is an
aromatic iodide. In some embodiments, suitable palladium-catalyzed
cross-coupling reaction conditions include
Pd(PPh.sub.3).sub.2Cl.sub.2, a copper catalyst, with an appropriate
base, for an appropriate time and at an appropriate temperature. In
some embodiments, the copper catalyst is CuI. In some embodiments,
the base is an amine base, such as TEA. In some embodiments, the
appropriate time and appropriate temperature is about one hour at
about 80.degree. C. to about 90.degree. C. or about 70.degree. C.
to about 90.degree. C.
[0407] In some embodiments, R.sup.10 or R.sup.11 is a protected
alcohol. In some embodiments, R.sup.10 or R.sup.11 is an alcohol
protected with a silyl ether. In some embodiments, protecting
groups are removed to produce a free alcohol using suitable
deprotection conditions including appropriate solvent, temperature
and time to produce XIII-3. In some embodiments, suitable
deprotection conditions include the use of aqueous HCl. In some
embodiments, the appropriate solvent is water, THF, methanol, or a
combination of solvents. In some embodiments, the appropriate time
at the appropriate temperature is about 30 min to about 1 hour at
about 0.degree. C. to about rt.
[0408] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
14.
##STR00591##
[0409] In Scheme 14, substituent X.sup.1 and R.sup.8 are as
described herein.
[0410] In some embodiments, XIV-3 is prepared from reacting amide
XIV-2 and bromide XIV-1 under appropriate addition/cyclization
conditions. In some embodiments, addition/cyclization conditions
include a suitable solvent, at a suitable temperature for an
appropriate amount of time. In some embodiments, the suitable
solvent is toluene. In some embodiments, the suitable temperature
for a suitable time is about 110.degree. C. for about
overnight.
[0411] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
15.
##STR00592##
[0412] In Scheme 15, substituent X.sup.1 and R.sup.8 are as
described herein.
[0413] In some embodiments, chloride XV-2 is reacted with acetylene
XV-1 under suitable metal-catalyzed cross-coupling reaction
conditions to provide XV-3. In some embodiments, suitable
metal-catalyzed cross-coupling conditions include palladium. In
some embodiments, suitable palladium-catalyzed cross-coupling
reaction conditions include Pd(PPh.sub.3).sub.2Cl.sub.2, a copper
catalyst, with an appropriate base, in an appropriate solvent, for
an appropriate time and at an appropriate temperature. In some
embodiments, the copper catalyst is CuI. In some embodiments, the
base is an amine base, such as TEA. In some embodiments, a suitable
solvent is THF. In some embodiments, the appropriate time and
appropriate temperature is about one hour at about rt.
[0414] In some embodiments, acetylene XV-3 is reacted with a
suitable aromatic halide XV-4 under suitable metal-catalyzed
cross-coupling reaction conditions in the presence of TBAF to
provide XV-5. In some embodiments, suitable metal-catalyzed
cross-coupling conditions include palladium. In some embodiments,
the aromatic halide is an aromatic iodide. In some embodiments,
suitable palladium-catalyzed cross-coupling reaction conditions
include Pd(PPh.sub.3).sub.2Cl.sub.2, a ligand, a copper catalyst,
in an appropriate solvent, with an appropriate base, for an
appropriate time and at an appropriate temperature. In some
embodiments, the copper catalyst is Cut In some embodiments, an
appropriate ligand is a phosphine ligand. In some embodiments, an
appropriate ligand is PPh.sub.3. In some embodiments, the base is
an amine base, such as TEA. In some embodiments, the appropriate
solvent is DMF. In some embodiments, the appropriate temperature is
60.degree. C. In some embodiments, TBAF is added and the reaction
is maintained at 60.degree. C. for the appropriate amount of time.
In some embodiments, the appropriate time is about 3 hours.
[0415] In some embodiments, compound XV-6 is prepared from reaction
of XV-5 and a thiocyanate under conjugate addition conditions. In
some embodiments, conjugate addition conditions include use of a
suitable thiocyanate salt in a suitable solvent for a suitable time
at a suitable temperature. In some embodiments, a suitable
thiocyanate salt is NH.sub.4SCN. In some embodiments, a suitable
solvent is methyl tert-butyl ether. In some embodiments, a suitable
time is about overnight. In some embodiments, a suitable
temperature is 60.degree. C.
[0416] In some embodiments, compound XV-7 is prepared from reaction
of XV-6 and an ammonia source for a suitable time at a suitable
temperature. In some embodiments, a suitable ammonia source is
NH.sub.3. In some embodiments, a suitable temperature is
-78.degree. C. In some embodiments, a suitable time is about 2
hours. In some embodiments, the reaction is further warmed to a
suitable temperature, such as about rt.
[0417] In some embodiments, intermediates used in the preparation
of compounds described herein are prepared as outlined in Scheme
16.
##STR00593##
[0418] In Scheme 16, substituent X.sup.1 and R.sup.8 are as
described herein. In some embodiments, X is halo, such as bromo or
chloro.
[0419] In some embodiments, when X is bromo, a-bromoketone XVI-2 is
obtained from subjecting ketone XVI-1 under suitable bromination
conditions. In some embodiments, suitable bromination conditions
include bromine, HBr, and acetic acid for a suitable time at a
suitable temperature. In some embodiments, the suitable time is
about overnight. In some embodiments, a suitable temperature is
about room temperature.
[0420] Alternatively, in some embodiments, .alpha.-haloketone XVI-2
is prepared from acid XVI-5. In some embodiments, XVI-5 is treated
with (COCl).sub.2 in a suitable solvent for a suitable time at a
suitable temperature to provide an intermediate acid chloride. In
some embodiments, the suitable solvent is DMF and DCM. In some
embodiments, the suitable time is about 2.5 hours. In some
embodiments, a suitable temperature is about 0.degree. C. to about
room temperature. In some embodiments, the intermediate acid
chloride is treated with TMSCHN.sub.2 in a suitable solvent for a
suitable time at a suitable temperature to provide
.alpha.-diazocarbonyl XVI-6. In some embodiments, the suitable
solvent is THF/ACN. In some embodiments, the suitable time is about
1 hour. In some embodiments, a suitable temperature is about
0.degree. C. to about room temperature.
[0421] In some embodiments, when X is bromo, .alpha.-diazocarbonyl
XVI-6 is treated with HBr/H.sub.2O in a suitable solvent for a
suitable time at a suitable temperature to provide
.alpha.-bromoketone XVI-2. In some embodiments, the suitable
solvent is THF/ACN. In some embodiments, the suitable time is about
30 minutes. In some embodiments, a suitable temperature is about
0.degree. C. to about room temperature.
[0422] In some embodiments, when X is chloro, .alpha.-diazocarbonyl
XVI-6 is treated with concentrated HCl in a suitable solvent for a
suitable time at a suitable temperature to provide
.alpha.-chloroketone XVI-2. In some embodiments, the suitable
solvent is THF/ACN. In some embodiments, the suitable time is about
30 minutes. In some embodiments, a suitable temperature is about
0.degree. C. to about room temperature.
[0423] In some embodiments, .alpha.-haloketone XVI-2 is treated
with amide XVI-3 and AgOTf in a suitable solvent for a suitable
time at a suitable temperature to provide XVI-4. In some
embodiments, the suitable solvent is EtOAc or dioxane. In some
embodiments, the suitable time is about overnight. In some
embodiments, a suitable temperature is about 70.degree. C. or about
100.degree. C.
[0424] In some embodiments, XVI-4 is subjected under
palladium-catalyzed cross coupling reaction conditions in the
presence of a suitable ammonia source to provide XVI-7. In some
embodiments, the suitable ammonia source is LiHMDS. In some
embodiments, suitable palladium-catalyzed cross-coupling reaction
conditions include Pd.sub.2(dba).sub.3 with an appropriate ligand
in an appropriate solvent for an appropriate time at an appropriate
temperature. In some embodiments, the appropriate ligand is X-Phos.
In some embodiments, the appropriate solvent is dioxane or THF. In
some embodiments, the appropriate time and appropriate temperature
is about 2 hours to about overnight at about 100.degree. C. In some
embodiments, the appropriate time and appropriate temperature is
about overnight at about 60.degree. C.
[0425] Additional procedures for the preparation of alternative
ring A groups not shown in the preceding schemes are known, and are
described in: Gangloff, A. R., et al. Synthesis of
3,5-disubstituted 1,2,4-oxadiazoles using tetrabutylammonium
fluoride as a mild and efficient catalyst, Tetrahedron Letters
(2001), 42(8), 1441-1443; Ramanathan, Mani, et al. One-Pot
Reactions for Synthesis of 2,5-Substituted Tetrazoles from
Aryldiazonium Salts and Amidines, Organic Letters (2015), 17(23),
5886-5889; Vallin, Karl S. A. et al., Efficient Chemoenzymatic
Dynamic Kinetic Resolution of 1-Heteroaryl Ethanols, Journal of
Organic Chemistry (2009), 74(24), 9328-9336; Shen, Lan et al,
Synthesis and structure-activity relationships of
thiadiazole-derivatives as potent and orally active peroxisome
proliferator-activated receptors ?/? dual agonists, Bioorganic
& Medicinal Chemistry, 16(6), 3321-3341; 2008; Genin, Michael
J. et al, Discovery of
6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidi-
n-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist
for the Treatment of Dyslipidemia, Journal of Medicinal Chemistry
(2015) 58(24), 9768-9772; Li, Xiaobing et al, PCT Int. Appl.,
2005113522, 01 Dec 2005 (Preparation of azole carboxamides as
inhibitors of bacterial type III protein secretion systems);
Hamada, Nagwa Mohamed Mahrous et al, Synthesis and antimicrobial
evaluation of some heterocyclic chalcone derivatives, Molecules,
16, 2304-2312; 2011; Mokale, Santosh N. et al Synthesis and in-vivo
hypolipidemic activity of some novel substituted phenyl isoxazol
phenoxy acetic acid derivatives, Bioorganic & Medicinal
Chemistry Letters, 24(9), 2155-2158; 2014; Jursic, Branko S. et.
al. Preparation of 5-substituted 2-methyl-1,3,4-oxadiazoles from
5-substituted tetrazoles and acetic anhydride, Synthetic
Communications (1994), 24(11), 1575-82.
[0426] In some embodiments, compounds are prepared as described in
the Examples.
Certain Terminology
[0427] Unless otherwise stated, the following terms used in this
application have the definitions given below. The use of the term
"including" as well as other forms, such as "include", "includes,"
and "included," is not limiting. The section headings used herein
are for organizational purposes only and are not to be construed as
limiting the subject matter described.
[0428] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x. By way of example only, a
group designated as "C.sub.1-C.sub.4" indicates that there are one
to four carbon atoms in the moiety, i.e. groups containing 1 carbon
atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by
way of example only, "C.sub.1-C.sub.4 alkyl" indicates that there
are one to four carbon atoms in the alkyl group, i.e., the alkyl
group is selected from among methyl, ethyl, propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, and t-butyl.
[0429] An "alkyl" group refers to an aliphatic hydrocarbon group.
The alkyl group is branched or straight chain. In some embodiments,
the "alkyl" group has 1 to 10 carbon atoms, i.e. a
C.sub.1-C.sub.10alkyl. Whenever it appears herein, a numerical
range such as "1 to 10" refers to each integer in the given range;
e.g., "1 to 10 carbon atoms" means that the alkyl group consist of
1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5
carbon atoms,6 carbon atoms, etc., up to and including 10 carbon
atoms, although the present definition also covers the occurrence
of the term "alkyl" where no numerical range is designated. In some
embodiments, an alkyl is a C.sub.1-C.sub.6alkyl. In one aspect the
alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, or t-butyl. Typical alkyl groups include, but are in no
way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
[0430] An "alkylene" group refers refers to a divalent alkyl group.
Any of the above mentioned monovalent alkyl groups may be an
alkylene by abstraction of a second hydrogen atom from the alkyl.
In some embodiments, an alkylene is a C.sub.1-C.sub.6alkylene. In
other embodiments, an alkylene is a C.sub.1-C.sub.4alkylene. In
certain embodiments, an alkylene comprises one to four carbon atoms
(e.g., C.sub.1-C.sub.4 alkylene). In other embodiments, an alkylene
comprises one to three carbon atoms (e.g., C.sub.1-C.sub.3
alkylene). In other embodiments, an alkylene comprises one to two
carbon atoms (e.g., C.sub.1-C.sub.2 alkylene). In other
embodiments, an alkylene comprises one carbon atom (e.g., C.sub.1
alkylene). In other embodiments, an alkylene comprises two carbon
atoms (e.g., C.sub.2 alkylene). In other embodiments, an alkylene
comprises two to four carbon atoms (e.g., C.sub.2-C.sub.4
alkylene). Typical alkylene groups include, but are not limited to,
--CH.sub.2--, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)--,
--CH.sub.2C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like.
[0431] "Deuteroalkyl" refers to an alkyl group where 1 or more
hydrogen atoms of an alkyl are replaced with deuterium.
[0432] The term "alkenyl" refers to a type of alkyl group in which
at least one carbon-carbon double bond is present. In one
embodiment, an alkenyl group has the formula --C(R).dbd.CR.sub.2,
wherein R refers to the remaining portions of the alkenyl group,
which may be the same or different. In some embodiments, R is H or
an alkyl. In some embodiments, an alkenyl is selected from ethenyl
(i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl,
pentadienyl, and the like. Non-limiting examples of an alkenyl
group include --CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CHCH.sub.3, --C(CH.sub.3).dbd.CHCH.sub.3, and
--CH.sub.2CH.dbd.CH.sub.2.
[0433] The term "alkynyl" refers to a type of alkyl group in which
at least one carbon-carbon triple bond is present. In one
embodiment, an alkenyl group has the formula --C.ident.C--R,
wherein R refers to the remaining portions of the alkynyl group. In
some embodiments, R is H or an alkyl. In some embodiments, an
alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl,
hexynyl, and the like. Non-limiting examples of an alkynyl group
include --C.ident.CH,
--C.ident.CCH.sub.3--C.ident.CCH.sub.2CH.sub.3,
--CH.sub.2C.ident.CH.
[0434] An "alkoxy" group refers to a (alkyl)O-- group, where alkyl
is as defined herein.
[0435] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, where x is 0 and y is 2, or where x is 1 and y is 1, or
where x is 2 and y is 0.
[0436] The term "aromatic" refers to a planar ring having a
delocalized .pi.-electron system containing 4n+2.pi. electrons,
where n is an integer. The term "aromatic" includes both
carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or
"heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term
includes monocyclic or fused-ring polycyclic (i.e., rings which
share adjacent pairs of carbon or nitrogen atoms) groups.
[0437] The term "carbocyclic" or "carbocycle" refers to a ring or
ring system where the atoms forming the backbone of the ring are
all carbon atoms. The term thus distinguishes carbocyclic from
"heterocyclic" rings or "heterocycles" in which the ring backbone
contains at least one atom which is different from carbon. In some
embodiments, at least one of the two rings of a bicyclic carbocycle
is aromatic. In some embodiments, both rings of a bicyclic
carbocycle are aromatic. Carbocycle includes cycloalkyl and
aryl.
[0438] As used herein, the term "aryl" refers to an aromatic ring
wherein each of the atoms forming the ring is a carbon atom. In one
aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl
is a phenyl. In some embodiments, an aryl is a
C.sub.6-C.sub.10aryl. Depending on the structure, an aryl group is
a monoradical or a diradical (i.e., an arylene group).
[0439] The term "cycloalkyl" refers to a monocyclic or polycyclic
aliphatic, non-aromatic group, wherein each of the atoms forming
the ring (i.e. skeletal atoms) is a carbon atom. In some
embodiments, cycloalkyls are spirocyclic or bridged compounds. In
some embodiments, cycloalkyls are optionally fused with an aromatic
ring, and the point of attachment is at a carbon that is not an
aromatic ring carbon atom. Cycloalkyl groups include groups having
from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are
selected from among cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,
spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some
embodiments, a cycloalkyl is a C.sub.3-C.sub.6cycloalkyl. In some
embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic
cycloalkyls include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Polycyclic cycloalkyls include, for example, adamantyl, norbornyl
(i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like
[0440] The term "halo" or, alternatively, "halogen" or "halide"
means fluoro, chloro, bromo or iodo. In some embodiments, halo is
fluoro, chloro, or bromo.
[0441] The term "haloalkyl" refers to an alkyl in which one or more
hydrogen atoms are replaced by a halogen atom. In one aspect, a
fluoroalkyl is a C.sub.1-C.sub.6fluoroalkyl.
[0442] The term "fluoroalkyl" refers to an alkyl in which one or
more hydrogen atoms are replaced by a fluorine atom. In one aspect,
a fluoroalkyl is a C.sub.1-C.sub.6fluoroalkyl. In some embodiments,
a fluoroalkyl is selected from trifluoromethyl, difluoromethyl,
fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
and the like.
[0443] The term "heteroalkyl" refers to an alkyl group in which one
or more skeletal atoms of the alkyl are selected from an atom other
than carbon, e.g., oxygen, nitrogen (e.g. --NH--, --N(alkyl)-,
sulfur, or combinations thereof. A heteroalkyl is attached to the
rest of the molecule at a carbon atom of the heteroalkyl. In one
aspect, a heteroalkyl is a C.sub.1-C.sub.6heteroalkyl.
[0444] The term "heteroalkylene" refers refers to a divalent
heteroalkyl group.
[0445] The term "heterocycle" or "heterocyclic" refers to
heteroaromatic rings (also known as heteroaryls) and
heterocycloalkyl rings (also known as heteroalicyclic groups)
containing one to four heteroatoms in the ring(s), where each
heteroatom in the ring(s) is selected from 0, S and N, wherein each
heterocyclic group has from 3 to 10 atoms in its ring system, and
with the proviso that any ring does not contain two adjacent O or S
atoms. In some embodiments, heterocycles are monocyclic, bicyclic,
polycyclic, spirocyclic or bridged compounds. Non-aromatic
heterocyclic groups (also known as heterocycloalkyls) include rings
having 3 to 10 atoms in its ring system and aromatic heterocyclic
groups include rings having 5 to 10 atoms in its ring system. The
heterocyclic groups include benzo-fused ring systems. Examples of
non-aromatic heterocyclic groups are pyrrolidinyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,
tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,
thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl,
thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,
diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,
pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,
dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,
3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl,
isoindolin-1-onyl, isoindoline-1,3-dionyl,
3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,
isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,
benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and
quinolizinyl. Examples of aromatic heterocyclic groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The
foregoing groups are either C-attached (or C-linked) or N-attached
where such is possible. For instance, a group derived from pyrrole
includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Further, a group derived from imidazole includes imidazol-1-yl or
imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or
imidazol-5-yl (all C-attached). The heterocyclic groups include
benzo-fused ring systems. Non-aromatic heterocycles are optionally
substituted with one or two oxo (.dbd.O) moieties, such as
pyrrolidin-2-one. In some embodiments, at least one of the two
rings of a bicyclic heterocycle is aromatic. In some embodiments,
both rings of a bicyclic heterocycle are aromatic.
[0446] The terms "heteroaryl" or, alternatively, "heteroaromatic"
refers to an aryl group that includes one or more ring heteroatoms
selected from nitrogen, oxygen and sulfur. Illustrative examples of
heteroaryl groups include monocyclic heteroaryls and bicyclic
heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
Bicyclic heteroaryls include indolizine, indole, benzofuran,
benzothiophene, indazole, benzimidazole, purine, quinolizine,
quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,
quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments,
a heteroaryl contains 0-4 N atoms in the ring. In some embodiments,
a heteroaryl contains 1-4 N atoms in the ring. In some embodiments,
a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in
the ring. In some embodiments, a heteroaryl contains 1-4 N atoms,
0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments,
heteroaryl is a C.sub.1-C.sub.9heteroaryl. In some embodiments,
monocyclic heteroaryl is a C.sub.1-C.sub.5heteroaryl. In some
embodiments, monocyclic heteroaryl is a 5-membered or 6-membered
heteroaryl. In some embodiments, bicyclic heteroaryl is a
C.sub.6-C.sub.9heteroaryl.
[0447] A "heterocycloalkyl" or "heteroalicyclic" group refers to a
cycloalkyl group that includes at least one heteroatom selected
from nitrogen, oxygen and sulfur. In some embodiments, a
heterocycloalkyl is fused with an aryl or heteroaryl. In some
embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl,
pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl,
imidazolidin-2-onyl, or thiazolidin-2-onyl. The term
heteroalicyclic also includes all ring forms of the carbohydrates,
including but not limited to the monosaccharides, the disaccharides
and the oligosaccharides. In one aspect, a heterocycloalkyl is a
C.sub.2-C.sub.10heterocycloalkyl. In another aspect, a
heterocycloalkyl is a C.sub.4-C.sub.10heterocycloalkyl. In some
embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring.
In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O
atoms and 0-1 S atoms in the ring.
[0448] The term "bond" or "single bond" refers to a chemical bond
between two atoms, or two moieties when the atoms joined by the
bond are considered to be part of larger substructure. In one
aspect, when a group described herein is a bond, the referenced
group is absent thereby allowing a bond to be formed between the
remaining identified groups.
[0449] The term "moiety" refers to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0450] The term "optionally substituted" or "substituted" means
that the referenced group is optionally substituted with one or
more additional group(s). In some other embodiments, optional
substituents are individually and independently selected from D,
halogen, --CN, --NH.sub.2, --NH(alkyl), --N(alkyl).sub.2, --OH,
--CO.sub.2H, --CO.sub.2alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(alkyl).sub.2,
--S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2NH(alkyl),
--S(.dbd.O).sub.2N(alkyl).sub.2, --CH.sub.2CO.sub.2H,
--CH.sub.2CO.sub.2alkyl, --CH.sub.2C(.dbd.O)NH.sub.2,
--CH.sub.2C(.dbd.O)NH(alkyl), --CH.sub.2C(.dbd.O)N(alkyl).sub.2,
--CH.sub.2S(.dbd.O).sub.2NH.sub.2,
--CH.sub.2S(.dbd.O).sub.2NH(alkyl),
--CH.sub.2S(.dbd.O).sub.2N(alkyl).sub.2, alkyl, alkenyl, alkynyl,
cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,
heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,
alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. The
term "optionally substituted" or "substituted" means that the
referenced group is optionally substituted with one or more
additional group(s) individually and independently selected from D,
halogen, --CN, --NH.sub.2, --NH(alkyl), --N(alkyl).sub.2, --OH,
--CO.sub.2H, --CO.sub.2alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(alkyl).sub.2,
--S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2NH(alkyl),
--S(.dbd.O).sub.2N(alkyl).sub.2, alkyl, cycloalkyl, fluoroalkyl,
heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl,
heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone, and arylsulfone. In some other
embodiments, optional substituents are independently selected from
D, halogen, --CN, --NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--OH, --CO.sub.2H, --CO.sub.2(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
--S(.dbd.O).sub.2NH.sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4fluoroalkoxy,
--SC.sub.1-C.sub.4alkyl, --S(.dbd.O)C.sub.1-C.sub.4alkyl, and
--S(.dbd.O).sub.2C.sub.1-C.sub.4alkyl. In some embodiments,
optional substituents are independently selected from D, halogen,
--CN, --NH.sub.2, --OH, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3, --OCH.sub.3, and
--OCF.sub.3. In some embodiments, substituted groups are
substituted with one or two of the preceding groups. In some
embodiments, substituted groups are substituted with one of the
preceding groups. In some embodiments, an optional substituent on
an aliphatic carbon atom (acyclic or cyclic) includes oxo
(.dbd.O).
[0451] The term "acceptable" with respect to a formulation,
composition or ingredient, as used herein, means having no
persistent detrimental effect on the general health of the subject
being treated.
[0452] The term "modulate" as used herein, means to interact with a
target either directly or indirectly so as to alter the activity of
the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0453] The term "modulator" as used herein, refers to a molecule
that interacts with a target either directly or indirectly. The
interactions include, but are not limited to, the interactions of
an agonist, partial agonist, an inverse agonist, antagonist,
degrader, or combinations thereof. In some embodiments, a modulator
is an agonist.
[0454] The terms "administer," "administering", "administration,"
and the like, as used herein, refer to the methods that may be used
to enable delivery of compounds or compositions to the desired site
of biological action. These methods include, but are not limited to
oral routes, intraduodenal routes, parenteral injection (including
intravenous, subcutaneous, intraperitoneal, intramuscular,
intravascular or infusion), topical and rectal administration.
Those of skill in the art are familiar with administration
techniques that can be employed with the compounds and methods
described herein. In some embodiments, the compounds and
compositions described herein are administered orally.
[0455] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0456] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered, which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result includes reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
comprising a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms. An appropriate
"effective" amount in any individual case is optionally determined
using techniques, such as a dose escalation study.
[0457] The terms "enhance" or "enhancing," as used herein, means to
increase or prolong either in potency or duration a desired effect.
Thus, in regard to enhancing the effect of therapeutic agents, the
term "enhancing" refers to the ability to increase or prolong,
either in potency or duration, the effect of other therapeutic
agents on a system. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of
another therapeutic agent in a desired system.
[0458] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound
described herein, or a pharmaceutically acceptable salt thereof,
and a co-agent, are both administered to a patient simultaneously
in the form of a single entity or dosage. The term "non-fixed
combination" means that the active ingredients, e.g. a compound
described herein, or a pharmaceutically acceptable salt thereof,
and a co-agent, are administered to a patient as separate entities
either simultaneously, concurrently or sequentially with no
specific intervening time limits, wherein such administration
provides effective levels of the two compounds in the body of the
patient. The latter also applies to cocktail therapy, e.g. the
administration of three or more active ingredients.
[0459] The terms "kit" and "article of manufacture" are used as
synonyms.
[0460] The term "subject" or "patient" encompasses mammals.
Examples of mammals include, but are not limited to, any member of
the Mammalian class: humans, non-human primates such as
chimpanzees, and other apes and monkey species; farm animals such
as cattle, horses, sheep, goats, swine; domestic animals such as
rabbits, dogs, and cats; laboratory animals including rodents, such
as rats, mice and guinea pigs, and the like. In one aspect, the
mammal is a human.
[0461] The terms "treat," "treating" or "treatment," as used
herein, include alleviating, abating or ameliorating at least one
symptom of a disease or condition, preventing additional symptoms,
inhibiting the disease or condition, e.g., arresting the
development of the disease or condition, relieving the disease or
condition, causing regression of the disease or condition,
relieving a condition caused by the disease or condition, or
stopping the symptoms of the disease or condition either
prophylactically and/or therapeutically.
Pharmaceutical Compositions
[0462] In some embodiments, the compounds described herein are
formulated into pharmaceutical compositions. Pharmaceutical
compositions are formulated in a conventional manner using one or
more pharmaceutically acceptable inactive ingredients that
facilitate processing of the active compounds into preparations
that are used pharmaceutically. Proper formulation is dependent
upon the route of administration chosen. A summary of
pharmaceutical compositions described herein is found, for example,
in Remington: The Science and Practice of Pharmacy, Nineteenth Ed
(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical
Dosage Forms, Marcel Decker, New York, N.Y., 1980; and
Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
(Lippincott Williams & Wilkins1999), herein incorporated by
reference for such disclosure.
[0463] In some embodiments, the compounds described herein are
administered either alone or in combination with pharmaceutically
acceptable carriers, excipients or diluents, in a pharmaceutical
composition. Administration of the compounds and compositions
described herein can be affected by any method that enables
delivery of the compounds to the site of action. These methods
include, though are not limited to delivery via enteral routes
(including oral, gastric or duodenal feeding tube, rectal
suppository and rectal enema), parenteral routes (injection or
infusion, including intraarterial, intracardiac, intradermal,
intraduodenal, intramedullary, intramuscular, intraosseous,
intraperitoneal, intrathecal, intravascular, intravenous,
intravitreal, epidural and subcutaneous), inhalational,
transdermal, transmucosal, sublingual, buccal and topical
(including epicutaneous, dermal, enema, eye drops, ear drops,
intranasal, vaginal) administration, although the most suitable
route may depend upon for example the condition and disorder of the
recipient. By way of example only, compounds described herein can
be administered locally to the area in need of treatment, by for
example, local infusion during surgery, topical application such as
creams or ointments, injection, catheter, or implant. The
administration can also be by direct injection at the site of a
diseased tissue or organ.
[0464] In some embodiments, pharmaceutical compositions suitable
for oral administration are presented as discrete units such as
capsules, cachets or tablets each containing a predetermined amount
of the active ingredient; as a powder or granules; as a solution or
a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In
some embodiments, the active ingredient is presented as a bolus,
electuary or paste.
[0465] Pharmaceutical compositions which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. Tablets may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with binders, inert diluents, or lubricating, surface active
or dispersing agents. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent. In some embodiments, the tablets are
coated or scored and are formulated so as to provide slow or
controlled release of the active ingredient therein. All
formulations for oral administration should be in dosages suitable
for such administration. The push-fit capsules can contain the
active ingredients in admixture with filler such as lactose,
binders such as starches, and/or lubricants such as talc or
magnesium stearate and, optionally, stabilizers. In soft capsules,
the active compounds may be dissolved or suspended in suitable
liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In some embodiments, stabilizers are added.
Dragee cores are provided with suitable coatings. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or Dragee coatings for
identification or to characterize different combinations of active
compound doses.
[0466] In some embodiments, pharmaceutical compositions are
formulated for parenteral administration by injection, e.g., by
bolus injection or continuous infusion. Formulations for injection
may be presented in unit dosage form, e.g., in ampoules or in
multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. The compositions
may be presented in unit-dose or multi-dose containers, for example
sealed ampoules and vials, and may be stored in powder form or in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example, saline or sterile
pyrogen-free water, immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
[0467] Pharmaceutical compositions for parenteral administration
include aqueous and non-aqueous (oily) sterile injection solutions
of the active compounds which may contain antioxidants, buffers,
bacteriostats and solutes which render the formulation isotonic
with the blood of the intended recipient; and aqueous and
non-aqueous sterile suspensions which may include suspending agents
and thickening agents. Suitable lipophilic solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase
the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or dextran. Optionally, the suspension may
also contain suitable stabilizers or agents which increase the
solubility of the compounds to allow for the preparation of highly
concentrated solutions.
[0468] Pharmaceutical compositions may also be formulated as a
depot preparation. Such long acting formulations may be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds may be formulated with suitable polymeric or
hydrophobic materials (for example, as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0469] For buccal or sublingual administration, the compositions
may take the form of tablets, lozenges, pastilles, or gels
formulated in conventional manner. Such compositions may comprise
the active ingredient in a flavored basis such as sucrose and
acacia or tragacanth.
[0470] Pharmaceutical compositions may also be formulated in rectal
compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter,
polyethylene glycol, or other glycerides.
[0471] Pharmaceutical compositions may be administered topically,
that is by non-systemic administration. This includes the
application of a compound of the present invention externally to
the epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does
not significantly enter the blood stream. In contrast, systemic
administration refers to oral, intravenous, intraperitoneal and
intramuscular administration.
[0472] Pharmaceutical compositions suitable for topical
administration include liquid or semi-liquid preparations suitable
for penetration through the skin to the site of inflammation such
as gels, liniments, lotions, creams, ointments or pastes, and drops
suitable for administration to the eye, ear or nose. The active
ingredient may comprise, for topical administration, from 0.001% to
10% w/w, for instance from 1% to 2% by weight of the
formulation.
[0473] Pharmaceutical compositions for administration by inhalation
are conveniently delivered from an insufflator, nebulizer
pressurized packs or other convenient means of delivering an
aerosol spray. Pressurized packs may comprise a suitable propellant
such as dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation,
pharmaceutical preparations may take the form of a dry powder
composition, for example a powder mix of the compound and a
suitable powder base such as lactose or starch. The powder
composition may be presented in unit dosage form, in for example,
capsules, cartridges, gelatin or blister packs from which the
powder may be administered with the aid of an inhalator or
insufflator.
[0474] In some embodiments, a compound disclosed herein is
formulated in such a manner that delivery of the compound to a
particular region of the gastrointestinal tract is achieved. For
example, a compound disclosed herein is formulated for oral
delivery with bioadhesive polymers, pH-sensitive coatings, time
dependent, biodegradable polymers, microflora activated systems,
and the like, in order to effect delivering of the compound to a
particular region of the gastrointestinal tract.
[0475] In some embodiments, a compound disclosed herein is
formulated to provide a controlled release of the compound.
Controlled release refers to the release of the compound described
herein from a dosage form in which it is incorporated according to
a desired profile over an extended period of time. Controlled
release profiles include, for example, sustained release, prolonged
release, pulsatile release, and delayed release profiles. In
contrast to immediate release compositions, controlled release
compositions allow delivery of an agent to a subject over an
extended period of time according to a predetermined profile. Such
release rates can provide therapeutically effective levels of agent
for an extended period of time and thereby provide a longer period
of pharmacologic response while minimizing side effects as compared
to conventional rapid release dosage forms. Such longer periods of
response provide for many inherent benefits that are not achieved
with the corresponding short acting, immediate release
preparations.
[0476] Approaches to deliver the intact therapeutic compound to the
particular regions of the gastrointestinal tract (e.g. such as the
colon), include:
[0477] (i) Coating with polymers: The intact molecule can be
delivered to the colon without absorbing at the upper part of the
intestine by coating of the drug molecule with the suitable
polymers, which degrade only in the colon.
[0478] (ii) Coating with pH-sensitive polymers: The majority of
enteric and colon targeted delivery systems are based on the
coating of tablets or pellets, which are filled into conventional
hard gelatin capsules. Most commonly used pH-dependent coating
polymers are methacrylic acid copolymers, commonly known as
Eudragit.RTM. S, more specifically Eudragit.RTM. L and
Eudragit.RTM. S. Eudragit.RTM. L100 and S 100 are copolymers of
methacrylic acid and methyl methacrylate.
[0479] (iii) Coating with biodegradable polymers;
[0480] (iv) Embedding in matrices;
[0481] (v) Embedding in biodegradable matrices and hydrogels;
[0482] (vi) Embedding in pH-sensitive matrices;
[0483] (vii) Timed release systems;
[0484] (viii) Redox-sensitive polymers;
[0485] (ix) Bioadhesive systems;
[0486] (x) Coating with microparticles;
[0487] (xi) Osmotic controlled drug delivery;
[0488] Another approach towards colon-targeted drug delivery or
controlled-release systems includes embedding the drug in polymer
matrices to trap it and release it in the colon. These matrices can
be pH-sensitive or biodegradable. Matrix-Based Systems, such as
multi-matrix (MMX)-based delayed-release tablets, ensure the drug
release in the colon.
[0489] Additional pharmaceutical approaches to targeted delivery of
therapeutics to particular regions of the gastrointestinal tract
are known. Chourasia M K, Jain S K, Pharmaceutical approaches to
colon targeted drug delivery systems., J Pharm Pharm Sci. 2003
January-April; 6(1):33-66. Patel M, Shah T, Amin A. Therapeutic
opportunities in colon-specific drug-delivery systems Crit Rev Ther
Drug Carrier Syst. 2007; 24(2):147-202. Kumar P, Mishra B. Colon
targeted drug delivery systems--an overview. Curr Drug Deliv. 2008
July; 5(3):186-98. Van den Mooter G. Colon drug delivery. Expert
Opin Drug Deliv. 2006 January; 3(1):111-25. Seth Amidon, Jack E.
Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery
Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015
August; 16(4): 731-741.
[0490] It should be understood that in addition to the ingredients
particularly mentioned above, the compounds and compositions
described herein may include other agents conventional in the art
having regard to the type of formulation in question, for example
those suitable for oral administration may include flavoring
agents.
Methods of Dosing and Treatment Regimens
[0491] In one embodiment, the compounds described herein, or a
pharmaceutically acceptable salt thereof, are used in the
preparation of medicaments for the treatment of diseases or
conditions in a mammal that would benefit from administration of a
FXR agonist. Methods for treating any of the diseases or conditions
described herein in a mammal in need of such treatment, involves
administration of pharmaceutical compositions that include at least
one compound described herein or a pharmaceutically acceptable
salt, active metabolite, prodrug, or pharmaceutically acceptable
solvate thereof, in therapeutically effective amounts to said
mammal.
[0492] Disclosed herein, are methods of administering a FXR agonist
in combination with an additional therapeutic agent. In some
embodiments, the additional therapeutic agent comprises a
therapeutic agent for treatment of diabetes or diabetes related
disorder or conditions, alcoholic or non-alcoholic liver disease,
inflammation related intestinal conditions, or cell proliferative
disorders.
[0493] In certain embodiments, the compositions containing the
compound(s) described herein are administered for prophylactic
and/or therapeutic treatments. In certain therapeutic applications,
the compositions are administered to a patient already suffering
from a disease or condition, in an amount sufficient to cure or at
least partially arrest at least one of the symptoms of the disease
or condition. Amounts effective for this use depend on the severity
and course of the disease or condition, previous therapy, the
patient's health status, weight, and response to the drugs, and the
judgment of the treating physician. Therapeutically effective
amounts are optionally determined by methods including, but not
limited to, a dose escalation and/or dose ranging clinical
trial.
[0494] In prophylactic applications, compositions containing the
compounds described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition. Such an amount is defined to be a
"prophylactically effective amount or dose." In this use, the
precise amounts also depend on the patient's state of health,
weight, and the like. When used in patients, effective amounts for
this use will depend on the severity and course of the disease,
disorder or condition, previous therapy, the patient's health
status and response to the drugs, and the judgment of the treating
physician. In one aspect, prophylactic treatments include
administering to a mammal, who previously experienced at least one
symptom of the disease being treated and is currently in remission,
a pharmaceutical composition comprising a compound described
herein, or a pharmaceutically acceptable salt thereof, in order to
prevent a return of the symptoms of the disease or condition.
[0495] In certain embodiments wherein the patient's condition does
not improve, upon the doctor's discretion, the compounds are
administered chronically, that is, for an extended period of time,
including throughout the duration of the patient's life in order to
ameliorate or otherwise control or limit the symptoms of the
patient's disease or condition.
[0496] In certain embodiments wherein a patient's status does
improve, the dose of drug being administered is temporarily reduced
or temporarily suspended for a certain length of time (i.e., a
"drug holiday"). In specific embodiments, the length of the drug
holiday is between 2 days and 1 year, including by way of example
only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12
days, 15 days, 20 days, 28 days, or more than 28 days. The dose
reduction during a drug holiday is, by way of example only, by
10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,
and 100%.
[0497] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, in
specific embodiments, the dosage or the frequency of
administration, or both, is reduced, as a function of the symptoms,
to a level at which the improved disease, disorder or condition is
retained. In certain embodiments, however, the patient requires
intermittent treatment on a long-term basis upon any recurrence of
symptoms.
[0498] The amount of a given agent that corresponds to such an
amount varies depending upon factors such as the particular
compound, disease condition and its severity, the identity (e.g.,
weight, sex) of the subject or host in need of treatment, but
nevertheless is determined according to the particular
circumstances surrounding the case, including, e.g., the specific
agent being administered, the route of administration, the
condition being treated, and the subject or host being treated.
[0499] In general, however, doses employed for adult human
treatment are typically in the range of 0.01 mg-5000 mg per day. In
one aspect, doses employed for adult human treatment are from about
1 mg to about 1000 mg per day. In one embodiment, the desired dose
is conveniently presented in a single dose or in divided doses
administered simultaneously or at appropriate intervals, for
example as two, three, four or more sub-doses per day.
[0500] In one embodiment, the daily dosages appropriate for the
compound described herein, or a pharmaceutically acceptable salt
thereof, are from about 0.01 to about 50 mg/kg per body weight. In
some embodiments, the daily dosage or the amount of active in the
dosage form are lower or higher than the ranges indicated herein,
based on a number of variables in regard to an individual treatment
regime. In various embodiments, the daily and unit dosages are
altered depending on a number of variables including, but not
limited to, the activity of the compound used, the disease or
condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the disease
or condition being treated, and the judgment of the
practitioner.
[0501] Toxicity and therapeutic efficacy of such therapeutic
regimens are determined by standard pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 and the ED.sub.50. The dose
ratio between the toxic and therapeutic effects is the therapeutic
index and it is expressed as the ratio between LD.sub.50 and
ED.sub.50. In certain embodiments, the data obtained from cell
culture assays and animal studies are used in formulating the
therapeutically effective daily dosage range and/or the
therapeutically effective unit dosage amount for use in mammals,
including humans. In some embodiments, the daily dosage amount of
the compounds described herein lies within a range of circulating
concentrations that include the ED.sub.50 with minimal toxicity. In
certain embodiments, the daily dosage range and/or the unit dosage
amount varies within this range depending upon the dosage form
employed and the route of administration utilized.
[0502] In any of the aforementioned aspects are further embodiments
in which the effective amount of the compound described herein, or
a pharmaceutically acceptable salt thereof, is: (a) systemically
administered to the mammal; and/or (b) administered orally to the
mammal; and/or (c) intravenously administered to the mammal; and/or
(d) administered by injection to the mammal; and/or (e)
administered topically to the mammal; and/or (f) administered
non-systemically or locally to the mammal.
[0503] In any of the aforementioned aspects are further embodiments
comprising single administrations of the effective amount of the
compound, including further embodiments in which (i) the compound
is administered once a day; or (ii) the compound is administered to
the mammal multiple times over the span of one day.
[0504] In any of the aforementioned aspects are further embodiments
comprising multiple administrations of the effective amount of the
compound, including further embodiments in which (i) the compound
is administered continuously or intermittently: as in a single
dose; (ii) the time between multiple administrations is every 6
hours; (iii) the compound is administered to the mammal every 8
hours; (iv) the compound is administered to the mammal every 12
hours; (v) the compound is administered to the mammal every 24
hours. In further or alternative embodiments, the method comprises
a drug holiday, wherein the administration of the compound is
temporarily suspended or the dose of the compound being
administered is temporarily reduced; at the end of the drug
holiday, dosing of the compound is resumed. In one embodiment, the
length of the drug holiday varies from 2 days to 1 year.
[0505] In certain instances, it is appropriate to administer at
least one compound described herein, or a pharmaceutically
acceptable salt thereof, in combination with one or more other
therapeutic agents.
[0506] In one embodiment, the therapeutic effectiveness of one of
the compounds described herein is enhanced by administration of an
adjuvant (i.e., by itself the adjuvant has minimal therapeutic
benefit, but in combination with another therapeutic agent, the
overall therapeutic benefit to the patient is enhanced). Or, in
some embodiments, the benefit experienced by a patient is increased
by administering one of the compounds described herein with another
agent (which also includes a therapeutic regimen) that also has
therapeutic benefit.
[0507] In one specific embodiment, a compound described herein, or
a pharmaceutically acceptable salt thereof, is co-administered with
a second therapeutic agent, wherein the compound described herein,
or a pharmaceutically acceptable salt thereof, and the second
therapeutic agent modulate different aspects of the disease,
disorder or condition being treated, thereby providing a greater
overall benefit than administration of either therapeutic agent
alone.
[0508] In any case, regardless of the disease, disorder or
condition being treated, the overall benefit experienced by the
patient may be additive of the two therapeutic agents or the
patient may experience a synergistic benefit.
[0509] In certain embodiments, different therapeutically-effective
dosages of the compounds disclosed herein will be utilized in
formulating pharmaceutical composition and/or in treatment regimens
when the compounds disclosed herein are administered in combination
with one or more additional agent, such as an additional
therapeutically effective drug, an adjuvant or the like.
Therapeutically-effective dosages of drugs and other agents for use
in combination treatment regimens is optionally determined by means
similar to those set forth hereinabove for the actives themselves.
Furthermore, the methods of prevention/treatment described herein
encompasses the use of metronomic dosing, i.e., providing more
frequent, lower doses in order to minimize toxic side effects. In
some embodiments, a combination treatment regimen encompasses
treatment regimens in which administration of a compound described
herein, or a pharmaceutically acceptable salt thereof, is initiated
prior to, during, or after treatment with a second agent described
herein, and continues until any time during treatment with the
second agent or after termination of treatment with the second
agent. It also includes treatments in which a compound described
herein, or a pharmaceutically acceptable salt thereof, and the
second agent being used in combination are administered
simultaneously or at different times and/or at decreasing or
increasing intervals during the treatment period. Combination
treatment further includes periodic treatments that start and stop
at various times to assist with the clinical management of the
patient.
[0510] It is understood that the dosage regimen to treat, prevent,
or ameliorate the condition(s) for which relief is sought, is
modified in accordance with a variety of factors (e.g. the disease,
disorder or condition from which the subject suffers; the age,
weight, sex, diet, and medical condition of the subject). Thus, in
some instances, the dosage regimen actually employed varies and, in
some embodiments, deviates from the dosage regimens set forth
herein.
[0511] For combination therapies described herein, dosages of the
co-administered compounds vary depending on the type of co-drug
employed, on the specific drug employed, on the disease or
condition being treated and so forth. In additional embodiments,
when co-administered with one or more other therapeutic agents, the
compound provided herein is administered either simultaneously with
the one or more other therapeutic agents, or sequentially.
[0512] In combination therapies, the multiple therapeutic agents
(one of which is one of the compounds described herein) are
administered in any order or even simultaneously. If administration
is simultaneous, the multiple therapeutic agents are, by way of
example only, provided in a single, unified form, or in multiple
forms (e.g., as a single pill or as two separate pills).
[0513] The compounds described herein, or a pharmaceutically
acceptable salt thereof, as well as combination therapies, are
administered before, during or after the occurrence of a disease or
condition, and the timing of administering the composition
containing a compound varies. Thus, in one embodiment, the
compounds described herein are used as a prophylactic and are
administered continuously to subjects with a propensity to develop
conditions or diseases in order to prevent the occurrence of the
disease or condition. In another embodiment, the compounds and
compositions are administered to a subject during or as soon as
possible after the onset of the symptoms. In specific embodiments,
a compound described herein is administered as soon as is
practicable after the onset of a disease or condition is detected
or suspected, and for a length of time necessary for the treatment
of the disease. In some embodiments, the length required for
treatment varies, and the treatment length is adjusted to suit the
specific needs of each subject. For example, in specific
embodiments, a compound described herein or a formulation
containing the compound is administered for at least 2 weeks, about
1 month to about 5 years.
[0514] In some embodiments, a FXR agonist is administered in
combination with an additional therapeutic agent for the treatment
of diabetes or diabetes related disorder or conditions.
[0515] In some instances, the additional therapeutic agent
comprises a statin, an insulin sensitizing drug, an insulin
secretagogue, an alpha-glucosidase inhibitor, a GLP agonist, a
DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin,
linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, or
dutoglpitin), a catecholamine (such as epinephrine, norepinephrine,
or dopamine), peroxisome proliferator-activated receptor
(PPAR)-gamma agonist (e.g., a thiazolidinedione (TZD) [such as
pioglitazone, rosiglitazone, rivoglitazone, or troglitazone],
aleglitazar, farglitazar, muraglitazar, or tesaglitazar), or a
combination thereof. In some cases, the statin is a HMG-CoA
reductase inhibitor. In other instances, additional therapeutic
agents include fish oil, fibrate, vitamins such as niacin, retinoic
acid (e.g., 9 cis-retinoic acid), nicotinamide ribonucleoside or
its analogs thereof, or combinations thereof. In some instances,
nicotinamide ribonucleoside or its analogs thereof, which promote
NAD+ production, a substrate for many enzymatic reactions including
p450s which is a target for FXR (e.g., see Yang et al., J. Med.
Chem. 50:6458-61, 2007).
[0516] In some embodiments, a FXR agonist is administered in
combination with an additional therapeutic agent such as a statin,
an insulin sensitizing drug, an insulin secretagogue, an
alpha-glucosidase inhibitor, a GLP agonist, a DPP-4 inhibitor (such
as sitagliptin, vildagliptin, saxagliptin, linagliptin, anaglptin,
teneligliptin, alogliptin, gemiglptin, or dutoglpitin), a
catecholamine (such as epinephrine, norepinephrine, or dopamine),
peroxisome proliferator-activated receptor (PPAR)-gamma agonist
(e.g., a thiazolidinedione (TZD) [such as pioglitazone,
rosiglitazone, rivoglitazone, or troglitazone], aleglitazar,
farglitazar, muraglitazar, or tesaglitazar), or combinations
thereof, for the treatment of diabetes or diabetes related disorder
or conditions. In some embodiments, a FXR agonist is administered
in combination with an additional therapeutic agent such as fish
oil, fibrate, vitamins such as niacin, retinoic acid (e.g., 9
cis-retinoic acid), nicotinamide ribonucleoside or its analogs
thereof, or combinations thereof, for the treatment of diabetes or
diabetes related disorder or conditions.
[0517] In some embodiments, a FXR agonist is administered in
combination with a statin such as a HMG-CoA reductase inhibitor,
fish oil, fibrate, niacin or a combination thereof, for the
treatment of dyslipidemia.
[0518] In additional embodiments, a FXR agonist is administered in
combination with a vitamin such as retinoic acid for the treatment
of diabetes and diabetes related disorder or condition such as
lowering elevated body weight and/or lowering elevated blood
glucose from food intake.
[0519] In some embodiments, the farnesoid X receptor agonist is
administered with at least one additional therapy. In some
embodiments, the at least one additional therapy is a
glucose-lowering agent. In some embodiments, the at least one
additional therapy is an anti-obesity agent. In some embodiments,
the at least one additional therapy is selected from among a
peroxisome proliferator activated receptor (PPAR) agonist (gamma,
dual, or pan), a dipeptidyl peptidase (IV) inhibitor, a
glucagon-like peptide-1 (GLP-I) analog, insulin or an insulin
analog, an insulin secretagogue, a sodium glucose co-transporter 2
(SGLT2) inhibitor, a glucophage, a human amylin analog, a
biguanide, an alpha-glucosidase inhibitor, a meglitinide, a
thiazolidinedione, and sulfonylurea. In some embodiments, the at
least one additional therapy is metformin, sitagliptin,
saxaglitpin, repaglinide, nateglinide, exenatide, liraglutide,
insulin lispro, insulin aspart, insulin glargine, insulin detemir,
insulin isophane, and glucagon-like peptide 1, or any combination
thereof. In some embodiments, the at least one additional therapy
is a lipid-lowering agent. In certain embodiments, the at least one
additional therapy is administered at the same time as the
farnesoid X receptor agonist. In certain embodiments, the at least
one additional therapy is administered less frequently than the
farnesoid X receptor agonist. In certain embodiments, the at least
one additional therapy is administered more frequently than the
farnesoid X receptor agonist. In certain embodiments, the at least
one additional therapy is administered prior to administration of
the farnesoid X receptor agonist. In certain embodiments, the at
least one additional therapy is administered after administration
of the farnesoid X receptor agonist.
[0520] In some embodiments, a compound described herein, or a
pharmaceutically acceptable salt thereof, is administered in
combination with chemotherapy, anti-inflammatory agents, radiation
therapy, monoclonal antibodies, or combinations thereof.
[0521] In some embodiments, a FXR agonist is administered in
combination with an additional therapeutic agent for the treatment
of alcoholic or non-alcoholic liver disease. In some embodiments,
the additional therapeutic agent includes antioxidant,
corticosteroid, anti-tumor necrosis factor (TNF) or a combination
thereof.
[0522] In some embodiments, a FXR agonist is administered in
combination with an additional therapeutic agent such as
antioxidant, corticosteroid, anti-tumor necrosis factor (TNF), or a
combination thereof, for the treatment of alcoholic or
non-alcoholic liver disease. In some embodiments, a FXR agonist is
administered in combination with an antioxidant, a vitamin
precursor, a corticosteroid, an anti-tumor necrosis factor (TNF),
or a combination thereof, for the treatment of alcoholic or
non-alcoholic liver disease.
[0523] In some embodiments, a FXR agonist is administered in
combination with an additional therapeutic agent for the treatment
of inflammation related intestinal conditions. In some instances,
the additional therapeutic agent comprises an antibiotic (such as
metronidazole, vancomycin, and/or fidaxomicin), a corticosteroid,
or an additional anti-inflammatory or immuno-modulatory
therapy.
[0524] In some instances, a FXR agonist is administered in
combination with an additional therapeutic agent such as an
antibiotic, a corticosteroid, or an additional anti-inflammatory or
immuno-modulatory therapy, for the treatment of inflammation
related intestinal conditions. In some cases, a FXR agonist is
administered in combination with metronidazole, vancomycin,
fidaxomicin, corticosteroid, or combinations thereof, for the
treatment of inflammation related intestinal conditions.
[0525] As discussed above, inflammation is sometimes associated
with pseudomembranous colitis. In some instances, pseudomembranous
colitis is associated with bacterial overgrowth (such as C.
dificile overgrowth). In some embodiments, a FXR agonist is
administered in combination with an antibiotic such as
metronidazole, vancomycin, fidaxomicin, or a combination thereof,
for the treatment of inflammation associated with bacterial
overgrowth (e.g., pseudomembranous colitis).
[0526] In some embodiments, the FXR agonist is administered in
combination with an additional therapeutic agent for the treatment
of cell proliferative disorders. In some embodiments, the
additional therapeutic agent includes a chemotherapeutic, a
biologic (e.g., antibody, for example bevacizumab, cetuximab, or
panitumumab), a radiotherapeutic (e.g., FOLFOX, FOLFIRI, CapeOX,
5-FU, leucovorin, regorafenib, irinotecan, or oxaliplatin), or
combinations thereof.
[0527] In some embodiments, the FXR agonist is administered in
combination with an additional therapeutic agent for the treatment
of primary biliary cirrhosis. In some embodiments, the additional
therapeutic agent includes ursodeoxycholic acid (UDCA).
[0528] In some embodiments, a FXR agonist is administered in
combination with an additional therapeutic agent such as a
chemotherapeutic, a biologic, a radiotherapeutic, or combinations
thereof, for the treatment of a cell proliferative disorder. In
some instances, a FXR agonist is administered in combination with
an antibody (e.g., bevacizumab, cetuximab, or panitumumab),
chemotherapeutic, FOLFOX, FOLFIRI, CapeOX, 5-FU, leucovorin,
regorafenib, irinotecan, oxaliplatin, or combinations thereof, for
the treatment of a cell proliferative disorder.
EXAMPLES
[0529] The following examples are provided for illustrative
purposes only and not to limit the scope of the claims provided
herein.
[0530] As used above, and throughout the description of the
invention, the following abbreviations, unless otherwise indicated,
shall be understood to have the following meanings: [0531] ACN or
MeCN acetonitrile [0532] AcOH acetic acid [0533] Ac acetyl [0534]
BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [0535] Bn
benzyl [0536] BOC or Boc tert-butyl carbamate [0537] t-Bu
tert-butyl [0538] Cy cyclohexyl [0539] DBA or dba
dibenzylideneacetone [0540] CDI 1,1-carbonyldiimidazole [0541] DCE
dichloroethane (ClCH.sub.2CH.sub.2Cl) [0542] DCM dichloromethane
(CH.sub.2Cl.sub.2) [0543] DIPEA or DIEA diisopropylethylamine
[0544] DMAP 4-(N,N-dimethylamino)pyridine [0545] DME
1,2-dimethoxyethane [0546] DMF N,N-dimethylformamide [0547] DMA
N,N-dimethylacetamide [0548] DMSO dimethylsulfoxide [0549] Dppf or
dppf 1,1'-bis(diphenylphosphino)ferrocene [0550] EDC or EDCI
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0551]
EEDQ 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline [0552] eq
equivalent(s) [0553] Et ethyl [0554] Et.sub.2O diethyl ether [0555]
EtOH ethanol [0556] EtOAc ethyl acetate [0557] HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate [0558] HMPA hexamethylphosphoramide
[0559] HOBt 1-hydroxybenzotriazole [0560] HPLC high performance
liquid chromatography [0561] KHMDS potassium
bis(trimethylsilyl)amide [0562] NaHMDS sodium
bis(trimethylsilyl)amide [0563] LiHMDS lithium
bis(trimethylsilyl)amide [0564] LAH lithium aluminum anhydride
[0565] LCMS liquid chromatography mass spectrometry [0566] Me
methyl [0567] MeOH methanol [0568] MS mass spectroscopy [0569] Ms
mesyl [0570] MTBE methyl tert-butyl ether [0571] NBS
N-bromosuccinimide [0572] NMM N-methyl-morpholine [0573] NMP
N-methyl-pyrrolidin-2-one [0574] NMR nuclear magnetic resonance
[0575] OTf trifluoromethanesulfonate [0576] PCC pyridinium
chlorochromate [0577] PE petroleum ether [0578] Ph phenyl [0579]
PPTS pyridium p-toluenesulfonate [0580] iPr/i-Pr iso-propyl [0581]
TBS tert-butyldimethylsilyl [0582] TBAF tetra-n-butylammonium
fluoride [0583] TBAI tetra-n-butylammonium iodide [0584] RP-HPLC
reverse phase-high pressure liquid chromatography [0585] TFA
trifluoroacetic acid [0586] TEA triethylamine [0587] THF
tetrahydrofuran [0588] TLC thin layer chromatography [0589] TMEDA
N,N,N',N-tetramethylethylenediamine
Intermediate 1
6-Chloro-3-methoxypicolinonitrile
##STR00594##
[0590] Step 1: 2-Cyano-3-methoxypyridine 1-oxide
[0591] 3-Chloroperbenzoic acid (90.8 g, 447 mmol, 85% purity) was
added to a solution of 3-methoxypicolinonitrile (50 g, 373 mmol) in
DCE (500 mL) at rt. The reaction mixture was heated at 65.degree.
C. overnight, and then allowed to cool to rt. The mixture was
washed with NaHCO.sub.3 (5.times.300 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then triturated in
petroleum ether/EtOAc=5/1 (300 mL) to give
2-cyano-3-methoxypyridine 1-oxide (50 g, 89%) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.95 (d, 1H), 7.37 (t,
1H), 6.90 (d, 1H), 4.03 (s, 3H); LCMS: 151.0 [M+H].sup.+.
Step 2: 6-Chloro-3-methoxypicolinonitrile
[0592] A mixture of 2-cyano-3-methoxypyridine 1-oxide (30 g, 200
mmol) and POCl.sub.3 (333 g, 2.17 mol) was heated to 100.degree. C.
for 2 h under N.sub.2. The mixture was concentrated to dryness,
diluted with NaHCO.sub.3 (300 mL), extracted with EtOAc
(2.times.100 mL). The organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and then purified by
silica gel chromatography (petroleum ether/EtOAc=2/1) to give
6-chloro-3-methoxypicolinonitrile (20 g, 59%) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.51 (d, 1H), 7.38 (d,
1H), 3.99 (s, 3H); LCMS: 169.0 [M+H].sup.+.
Intermediate 2
5-Bromo-3-fluoro-1-methyl-1H-indazole
##STR00595##
[0594]
1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium
tetrafluoroborate (16.11 g, 45.48 mmol) was added to a solution of
5-bromo-1-methyl-1H-indazole (8.00 g, 37.90 mmol) in CH.sub.3CN (80
mL) at rt. The mixture was stirred at 80.degree. C. overnight,
quenched with H.sub.2O (50 mL) at rt, and then diluted with EtOAc
(50 mL). The mixture was extracted with EtOAc (3.times.50 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (petroleum
ether/EtOAc=50 to 5:1) to give
5-bromo-3-fluoro-1-methyl-1H-indazole (3.95 g, 46%) as a white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.93 (s, 1H),
7.53-7.65 (m, 2H), 3.90 (s, 3H).
Intermediate 3
trans-4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde
##STR00596##
[0595] Step 1:
8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene
[0596] A mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid
pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g,
113 mmol), Pd(dppf)Cl.sub.2 (1.38 g, 1.89 mmol), dioxane (470 mL)
and 1 M Na.sub.2CO.sub.3 (282 mL, 282 mmol) was degassed with 3
vacuum/N.sub.2 cycles, stirred at 50.degree. C. for 2.5 h, and then
allowed to cool to rt. The mixture was diluted with EtOAc (500 mL)
and washed with saturated NaHCO.sub.3 (2.times.500 mL). The aqueous
layers were back extracted with EtOAc (200 mL). The combined EtOAc
extracts were dried (Na.sub.2SO.sub.4), filtered, concentrated and
purified by silica gel chromatography (0-5% EtOAc in hexanes) to
give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene
(19.9 g, 81%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H),
3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H),
1.77 (t, 2H); LCMS: 261.1 [M+H].sup.+.
Step 2: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane
[0597] Palladium on carbon (10 wt %, 8.08 g, 7.59 mmol) was added
to a solution of
8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (19.8 g,
76.1 mmol) in EtOAc (300 mL) at rt under N.sub.2. The N.sub.2 inlet
was replaced with a balloon of Hz. The reaction was stirred for 4.5
h, filtered through Celite with EtOAc, and then concentrated to
give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (18.2
g; contains 13% ketone) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.00-6.95 (m, 2H), 6.81 (d, 1H), 3.91-3.84
(m, 4H), 3.73 (s, 3H), 2.49-2.42 (m, 1H), 2.11 (s, 3H), 1.76-1.68
(m, 4H), 1.67-1.55 (m, 4H); LCMS: 263.1 [M+H].sup.+.
Step 3: 4-(4-Methoxy-3-methylphenyl)cyclohexanone
[0598] Formic acid (96%, 14 mL, 356 mmol) and then H.sub.2O (2.20
mL, 122 mmol) were added to a solution of
8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (18.2 g) in
toluene (60 mL) at rt under N.sub.2. The reaction was heated at
120.degree. C. for 4 hours, allowed to cool to rt, and then poured
into H.sub.2O (200 mL) and toluene (200 mL). The toluene layer was
washed (200 mL H.sub.2O and then 200 mL saturated NaHCO.sub.3). The
aqueous layers were back extracted with toluene (100 mL). The
combined toluene extracts were dried (Na.sub.2SO.sub.4), filtered
and concentrated to give 4-(4-methoxy-3-methylphenyl)cyclohexanone
(15.5 g, 88% over 2 steps) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.08-7.03 (m, 2H), 6.84 (d, 1H), 3.74 (s,
3H), 3.00-2.91 (m, 1H), 2.61-2.51 (m, 2H), 2.28-2.20 (m, 2H), 2.12
(s, 3H), 2.06-1.98 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 219.0
[M+H].sup.+.
Step 4:
1-Methoxy-4-(4-(methoxymethylene)cyclohexyl)-2-methylbenzene
[0599] A mixture of (methoxymethyl)triphenyl phosphonium chloride
(35.74 g, 104.3 mmol) and THF (260 mL) under N.sub.2 was cooled to
-2.2.degree. C. in an ice/brine bath. Sodium
bis(trimethylsilyl)amide solution (2 M in THF, 50 mL, 100 mmol) was
added dropwise via addition funnel over 12 min (internal
temp.ltoreq.0.6.degree. C.) with THF rinsing (5 mL). The reaction
was stirred for 30 min, and then
4-(4-methoxy-3-methylphenyl)cyclohexanone (14.5 g, 66.6 mmol) was
added portionwise over 5 min (exotherm to 7.3.degree. C.). Residual
cyclohexanone was rinsed into the reaction with THF (20 mL). The
reaction was stirred at 0.degree. C. for 25 min, and then poured
into H.sub.2O (400 mL) and toluene (400 mL). The toluene layer was
washed (400 mL H.sub.2O), dried (Na.sub.2SO.sub.4), filtered,
concentrated and purified by silica gel chromatography (0-5% EtOAc
in hexanes) to give
1-methoxy-4-(4-(methoxymethylene)cylcohexyl)-2-methylbenzene (15.6
g, 95%) as a pale gold oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 6.99-6.94 (m, 2H), 6.80 (d, 1H), 5.87 (s, 1H), 3.73 (s,
3H), 3.48 (s, 3H), 2.78-2.71 (m, 1H), 2.56-2.44 (m, 1H), 2.10 (s,
3H), 2.17-2.09 (m, 1H), 2.01-1.91 (m, 1H), 1.83-1.73 (m, 2H),
1.72-1.63 (m, 1H), 1.38-1.23 (m, 2H); LCMS: 247.1 [M+H].sup.+.
Step 5: 4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde
[0600] Formic acid (96%, 12.5 mL, 331 mmol) and then water (2.5 mL,
139 mmol) were added to a solution of
1-methoxy-4-(4-(methoxymethylene)cylcohexyl)-2-methylbenzene (16.05
g, 65.15 mmol) in toluene (130 mL) under N.sub.2. The reaction was
heated at 120.degree. C. for 2 h, allowed to cool to rt, and then
poured into 350 mL EtOAc and 350 mL H.sub.2O. The organic layer was
washed with 350 mL H.sub.2O, dried (Na.sub.2SO.sub.4), filtered and
concentrated to give
4-(4-methoxy-3-methylphenyl)cyclohexanecarbaldehyde (15.05 g) as a
1:1 mixture of stereoisomers.
Step 6:
trans-4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde
[0601] Aqueous sodium hydroxide (3.2 M, 31 mL, 99 mmol) was added
to the crude mixture from Step 5 (14.68 g, 63.19 mmoL), toluene (60
mL) and ethanol (250 mL) at rt. The reaction was stirred for 5.5
hours (equilibration monitored by NMR) and then poured into 350 mL
H.sub.2O and 350 mL EtOAc. The organic layer was washed with 350 mL
H.sub.2O, and the aqueous layers were back extracted with 150 mL
EtOAc. The combined extracts were dried (Na.sub.2SO.sub.4),
filtered, concentrated and purified by silica gel chromatography
(0-5% EtOAc in hexanes) to give
trans-4-(4-methoxy-3-methylphenyl)cyclohexanecarbaldehyde (10.17 g,
69%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.60 (s, 1H), 7.01-6.97 (m, 2H), 6.82 (d, 1H), 3.74 (s, 3H),
2.41-2.27 (m, 2H), 2.12 (s, 3H), 2.03-1.96 (m, 2H), 1.87-1.80 (m,
2H), 1.51-1.39 (m, 2H), 1.35-1.23 (m, 2H); LCMS: 233.0
[M+H].sup.+.
[0602] The Intermediates below were synthesized from the
appropriate aryl halide (SM or Intermediate) following the
procedures described for Intermediate 3.
TABLE-US-00003 Int Structure Name [M + H].sup.+ 3.01 ##STR00597##
trans-4-(6-(Dimethylamino)pyridin-3- yl)cyclohexanecarbaldehyde
233.0 3.02.sup.10,11,12 ##STR00598##
trans-4-(5-Methoxy-6-methylpyridin- 2-yl)cyclohexanecarbaldehyde
234.1 3.03.sup.9,10,11 ##STR00599##
trans-4-(6-Methoxy-5-methylpyridin- 3-yl)cyclohexanecarbaldehyde
234.1 3.04.sup.3,7,10 ##STR00600##
trans-4-(5-Chloro-6-methoxypyridin- 3-yl)cyclohexanecarbaldehyde
254.4 3.05 ##STR00601## 5-(trans-4-Formylcyclohexyl)-2-
methoxybenzonitrile 244.0 3.06.sup.1,8,10,11,12 ##STR00602##
6-(trans-4-formylcyclohexyl)-3- methoxypicolinonitrile 245.1
3.07.sup.6,10 ##STR00603## trans-4-(3-Fluoro-1-methyl-1H-
indazol-5- yl)cyclohexanecarbaldehyde 261.2 Alternate conditions:
Step 1: .sup.1EtOH, DME, 100.degree. C., 5 h; .sup.2EtOH, dioxane,
100.degree. C., overnight; .sup.3Cs.sub.2CO.sub.3, dioxane,
100.degree. C., 6 h; .sup.4Pd(PPh.sub.3).sub.4, 100.degree. C., 5
h; .sup.5Pd(PPh.sub.3).sub.4, CH.sub.3CN/H.sub.2O, reflux,
overnight; Step 2: .sup.6CH.sub.3OH; .sup.7HCl, EtOAc; Step 3:
.sup.8PPTS, acetone, H.sub.2O, 60.degree. C. 10 h; .sup.93M HCl,
THF, 60.degree. C., 3 h to overnight; Step 4: .sup.10LiHMDS (1M
THF), 0.degree. C. or rt, 0.5-2 h; Step 5: .sup.113M HCl, THF, rt
or 60.degree. C., 1-6 h; Step 6: .sup.12NaOMe, CH.sub.3OH, rt, 4 h
to overnight.
Intermediate 4
trans-4-(3-Chloro-4-methoxyphenyl)cyclohexanecarbaldehyde
##STR00604##
[0603] Step 1:
8-(3-Chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decan-8-ol
[0604] To a 3-necked round bottom flask was added
4-bromo-2-chloro-1-methoxy-benzene (45.00 g, 203.18 mmol) and THF
(450 mL), n-Butyllithium (2.5 M in hexanes, 90.21 mL, 1.11 eq) was
added at -78.degree. C. The mixture was stirred for 2 h at
-78.degree. C. A solution of 1,4-dioxaspiro[4.5]decan-8-one (34.91
g, 223.50 mmol) in THF (90 mL) was added dropwise to the reaction
mixture. The resulting mixture was stirred for 3 h at -78.degree.
C. The reaction was quenched with aqueous NH.sub.4Cl (100 mL) and
extracted with EtOAc (500 mL). The organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
washed with hexanes (350 mL), filtered and dried under high vacuum.
The solid was triturated with hexanes (15 mL), filtered and dried
under high vacuum to give
8-(3-chloro-4-methoxy-phenyl)-1,4-dioxaspiro[4.5]decan-8-ol (37 g,
61%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.31 (d, 1H), 7.29 (dd, 1H), 7.10 (d, 1H), 3.90-3.92 (m, 4H), 3.89
(s, 3H), 1.99-2.02 (m, 4H), 1.70-1.73 (m, 4H); LCMS: 281.2
[M-OH].sup.+.
Step 2: 8-(3-Chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane
[0605] A solution of triethylsilane (19.26 g, 165.6 mmol), TFA
(25.18 g, 220.8 mmol), and CH.sub.2Cl.sub.2 (100 mL) was added
dropwise to a solution of
8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (31.0 g,
110.4 mmol) and CH.sub.2Cl.sub.2 (200 mL) at 0.degree. C. The
reaction mixture was stirred at rt overnight and then cooled to
0.degree. C. The pH was adjusted to .about.8 with aqueous
NaHCO.sub.3 and the mixture was extracted with CH.sub.2Cl.sub.2
(2.times.100 mL). The organic layer was dried (Na.sub.2SO.sub.4),
filtered, and concentrated to dryness to give
8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane, containing
a small amount of
8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene, (38 g,
crude) as a yellow oil. LCMS: 283.1 [M+H].sup.+.
Step 3: 4-(3-Chloro-4-methoxyphenyl)cyclohexanone
[0606] 8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane (38.0
g, 134 mmol), formic acid (32.3 g, 672 mmol), H.sub.2O (4.84 g, 269
mmol), and toluene (400 mL) was degassed with 3 vacuum/N.sub.2
cycles, stirred at 130.degree. C. overnight and then washed with
H.sub.2O (200 mL) and sat'd NaHCO.sub.3 (200 mL). The combined
aqueous layers were extracted with toluene (300 mL). The organic
layer was dried (Na.sub.2SO.sub.4), filtered, and concentrated to
dryness. The residue was triturated (petroleum ether:EtOAc=10:1, 80
mL) to give 4-(3-chloro-4-methoxyphenyl)cyclohexanone, containing a
small amount of
3'-chloro-4'-methoxy-5,6-dihydro-[1,1'-biphenyl]-4(3H)-one, (20 g,
54%) as a light yellow solid. This solid (5.00 g, 21.12 mmol) was
added to a mixture of Pd/C (10 wt. %, 820 mg, 0.77 mmol), HCl (12
M, 1.00 mL), and EtOAc (100 mL). The resulting mixture was degassed
with 3 vacuum/H.sub.2 cycles, stirred at rt for 30 min under
H.sub.2 (15 psi), filtered and then diluted with EtOAc (50 mL). The
mixture was washed water (100 mL) and washed with sat'd NaHCO.sub.3
(100 mL). The aqueous phase was extracted with EtOAc (100 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered,
and concentrated to dryness to give
4-(3-chloro-4-methoxyphenyl)cyclohexanone (4.60 g, 84%) as a yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.24 (d, 1H),
7.09 (dd, 1H), 6.88 (d, 1H), 3.90 (s, 3H), 2.88-3.05 (m, 1H),
2.44-2.54 (m, 4H), 2.12-2.25 (m, 2H), 1.79-1.96 (m, 2H); LCMS:
239.1 [M+H].sup.+.
Step 4:
2-Chloro-1-methoxy-4-(4-(methoxymethylene)cyclohexyl)benzene
[0607] Lithium bis(trimethylsilyl)amide (1 M, 36 mL) was added
dropwise to a mixture of methoxymethyl(triphenyl)phosphonium
chloride (12.24 g, 35.71 mmol) and THF (80 mL) at 0.degree. C. The
mixture was stirred for 2 h at 0.degree. C. A solution of
4-(3-chloro-4-methoxy-phenyl)cyclohexanone (5.50 g, 23.04 mmol) in
THF (20 mL) was added dropwise at 0.degree. C. The resulting
mixture was stirred for 3 h at 0.degree. C. The reaction mixture
was quenched with H.sub.2O (100 mL) and extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with
brine (200 mL), dried (Na.sub.2SO.sub.4), filtered, concentrated,
and purified by silica gel chromatography (petroleum
ether:EtOAc=20:1) to give
2-chloro-1-methoxy-4-(4-(methoxymethylene)cyclohexyl)benzene (5 g,
77%) as yellow oil. LCMS: 267.1 [M+H].sup.+.
Step 5: 4-(3-Chloro-4-methoxyphenyl)cyclohexanecarbaldehyde
[0608] A mixture of
2-chloro-1-methoxy-4-(4-(methoxymethylene)cyclohexyl)benzene (5.00
g, 18.74 mmol), formic acid (4.50 g, 93.7 mmol), H.sub.2O (675.5
mg, 37.48 mmol), and toluene (100 mL) was degassed with 3
vacuum/N.sub.2 cycles, stirred at 130.degree. C. overnight, allowed
to cool to rt, and then washed with H.sub.2O (200 mL), and washed
with sat'd NaHCO.sub.3 (200 mL). The combined aqueous layers were
extracted with toluene (300 mL). The organic layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to dryness to give
4-(3-chloro-4-methoxy-phenyl)cyclohexanecarbaldehyde (5.60 g,
crude), a mixture of cis/trans isomers, as a yellow oil.
Step 6:
trans-4-(3-Chloro-4-methoxyphenyl)cyclohexanecarbaldehyde
[0609] A solution of NaOH (992.6 mg, 24.82 mmol) in H.sub.2O (12
mL) was added to the crude mixture from Step 5 (5.60 g, 15.51
mmol), EtOH (90 mL), and toluene (15 mL). The mixture was stirred
at rt overnight, quenched with H.sub.2O (100 mL), and then
extracted with EtOAc (3.times.100 mL). The combined organic layers
were washed by brine (200 mL), dried (Na.sub.2SO.sub.4), filtered
and concentrated to dryness to give a residue. The residue was
purified by silica gel chromatography (petroleum ether:EtOAc=20:1)
and then triturated with MTBE (20 mL) to give
trans-4-(3-chloro-4-methoxyphenyl)cyclohexanecarbaldehyde (1.96 g,
49%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.60 (s, 1H), 7.27 (d, 1H), 7.16 (dd, 1H), 7.05 (d, 1H), 3.81 (s,
3H), 2.43 (m, 1H), 2.27-2.37 (m, 1H), 1.95-2.05 (m, 2H), 1.84 (m,
2H), 1.45 (m, 2H), 1.21-1.35 (m, 2H); LCMS: 253.1 [M+H].sup.+.
[0610] The Intermediate below was synthesized from
4-bromo-1-methoxy-2-methylbenzene following the procedures
described for Intermediate 4.
TABLE-US-00004 Int Structure Name [M + H].sup.+ 3 ##STR00605##
trans-4-(4-Methoxy-3- methylphenyl) cyclohexanecarbaldehyde 233.0
Alternate conditions: Step 1: -60.degree. C.; Step 2: 0.degree. C.,
1 h; Step 3a: THF in place of PhMe, 80.degree. C., 18 h; Step 3b:
no HCl, 30 psi H.sub.2, 18 h; Step 4: 15 h; Step 5: 3N HCl, THF,
60.degree. C., 1 h; Step 6: THF in place of PhMe.
Intermediate 5
4-(4-Methoxy-3-methylphenyl)pyridin[2.2.2]octane-1-carbaldehyde
##STR00606##
[0611] Step 1: Ethyl
4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
[0612] n-Butyllithium (2.5M in hexanes, 60 mL, 150.0 mmol) was
added dropwise to a solution of 4-bromo-1-methoxy-2-methylbenzene
(27.78 g, 138.2 mmol) in THF (300 mL) at -78.degree. C. The mixture
was stirred at -78.degree. C. for 1 h and then added dropwise to a
solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol)
and THF (300 mL) at -78.degree. C. The reaction mixture was stirred
at -78.degree. C. for 2 h, added to saturated NH.sub.4Cl (600 mL)
and then extracted with EtOAc (2.times.600 mL). The combined
organic extracts were washed (400 mL water and then 400 mL brine),
dried (Na.sub.2SO.sub.4), filtered, and concentrated. The crude was
purified by silica gel chromatography (petroleum ether/EtOAc=10/1)
to give ethyl
4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.9
g, 45%) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H),
3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s,
3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H); LCMS:
275.2 [M-OH].sup.+.
Step 2: Ethyl
4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
[0613] Boron trifluoride diethyl etherate (24.85 g, 84.03 mmol) was
added to a solution of ethyl
4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.90
g, 64.64 mmol), allyltrimethylsilane (11.82 g, 103.42 mmol), and
CH.sub.2Cl.sub.2 (400 mL) at -78.degree. C. The mixture was stirred
at -78.degree. C. for 1 h, stirred at rt overnight, and then added
to brine (200 mL) and CH.sub.2Cl.sub.2 (200 mL). The organic layer
was separated, washed (2.times.200 mL saturated NaHCO.sub.3 and
then 200 mL brine), dried (Na.sub.2SO.sub.4), filtered, and then
concentrated. The crude was purified by silica gel chromatography
(petroleum ether/EtOAc=20/1) to give ethyl
4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (15 g,
71%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.00-7.10 (m, 2H), 6.76 (d, 1H), 5.26-5.50 (m, 1H), 4.81-4.98 (m,
2H), 4.15 (q, 0.5H), 4.03 (q, 1.5H), 3.81 (s, 3H), 2.26-2.42 (m,
3H), 2.21 (s, 3H), 2.15 (d, 1.5H), 1.98 (d, 0.5H), 1.75-1.88 (m,
2.5H), 1.60-1.72 (m, 0.5H), 1.33-1.55 (m, 3H), 1.27 (t, 0.8H), 1.18
(t, 2.2H); LCMS: 339.3 [M+Na].sup.+.
Step 3: Ethyl
4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexane
carboxylate
[0614] Osmium tetroxide (0.1 M in tert-butanol, 7.6 mL, 0.76 mmol)
was added to a solution of ethyl
4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (4.81 g,
15.2 mmol), 4-methylmorpholine N-oxide (2.67 g, 22.8 mmol),
CH.sub.3CN (100 mL), and H.sub.2O (25 mL) at 0.degree. C. The
reaction was stirred at rt overnight, and saturated Na2SO.sub.3 (50
mL) was added. The mixture was stirred at rt for 30 min,
concentrated, dissolved in water (80 mL), and then extracted with
EtOAc (2.times.100 mL). The organic layers were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The reside was
purified by silica gel chromatography (petroleum ether/EtOAc=1/1)
to give ethyl
4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylat-
e (5.23 g, 94%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.05-7.16 (m, 2H), 6.78 (d, 1H), 4.06-4.17 (m, 0.5H),
3.95-4.05 (m, 1.5H), 3.80 (s, 3H), 3.48-3.66 (m, 1H), 3.18-3.32 (m,
2H), 2.40-2.53 (m, 2H), 2.27-2.37 (m, 1H), 2.19 (s, 3H), 1.80 (t,
3H), 1.32-1.68 (m, 7H), 1.24 (td, 0.8H), 1.17 (t, 2.2H); LCMS:
373.3 [M+Na].sup.+.
Step 4: Ethyl
4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarboxylate
[0615] Sodium periodate (3.83 g, 17.90 mmol) was added to a
solution of ethyl
4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarb-
oxylate (5.23 g, 14.9 mmol), THF (70 mL), and H.sub.2O (35 mL) at
0.degree. C. The mixture was stirred at rt overnight and added to
water (50 mL) and EtOAc (2.times.100 mL). The organic layer was
separated, washed (80 mL water and then 80 mL brine), dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by silica gel chromatography (petroleum ether/EtOAc=5/1)
to give ethyl
4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarboxylate
(3.95 g, 82%) as a yellow oil . .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 9.28-9.42 (m, 1H), 7.07-7.19 (m, 2H), 6.79 (d, 1H), 4.15
(q, 0.5H), 4.04 (q, 1.5H), 3.82 (s, 3H), 2.41-2.52 (m, 3H), 2.33
(s, 1H), 2.21 (s, 3H), 1.75-1.92 (m, 3H), 1.46-1.63 (m, 4H),
1.23-1.31 (t, 0.5H), 1.19 (t, 2.5H); LCMS: 341.3 [M+Na].sup.+.
Step 5: Ethyl
4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
[0616] Sodium borohydride (704 mg, 18.6 mmol) was added to a
solution of ethyl
4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarboxylate
(3.95 g, 12.41 mmol) and THF (100 mL) at 0.degree. C. The mixture
was stirred at 0.degree. C. for 1 h, stirred at rt overnight, and
then diluted with water (100 mL). The organic solvent was removed
under reduced pressure, and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.300 mL). The organic extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated The residue was
purified by silica gel chromatography (petroleum ether/EtOAc=3/1)
to give ethyl
4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
(3.11 g, 67%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 6.96-7.04 (m, 2H), 6.71 (d, 1H), 4.03-4.12 (q, 0.4H), 3.97
(q, 1.6H), 3.74 (s, 3H), 3.28-3.38 (m, 2H), 2.19-2.39 (m, 3H), 2.14
(s, 3H), 1.71-1.80 (m, 2H), 1.60-1.70 (m, 2H), 1.28-1.50 (m, 4H),
1.17-1.24 (t, 1H), 1.12 (t, 2H); LCMS: 343.2 [M+Na].sup.+.
Step 6: Ethyl
4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
[0617] A solution of triphenylphosphine (4.60 g, 17.54 mmol) and
CH.sub.2Cl.sub.2 (20 mL) was added dropwise to a solution of ethyl
4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
(2.81 g, 8.77 mmol), CBr.sub.4 (4.36 g, 13.16 mmol), and
CH.sub.2Cl.sub.2 (40 mL) at 0.degree. C. The mixture was stirred at
0.degree. C. for 1 h, stirred at rt overnight, and then
concentrated. The residue was purified by silica gel chromatography
(petroleum ether/EtOAc=20/1) to give ethyl
4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
(2.62 g, 77%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 6.96-7.08 (m, 2H), 6.77 (d, 1H), 4.15 (q, 0.3H), 4.03 (q,
1.7H), 3.81 (s, 3H), 2.91-3.06 (m, 2H), 2.24-2.41 (m, 3H),
2.15-2.24 (s, 3H), 1.95-2.06 (m, 2H), 1.77-1.87 (m, 2H), 1.34-1.53
(m, 4H), 1.27 (t, 1H), 1.18 (t, 2H); LCMS: 405.1 [M+Na].sup.+.
Step 7: Ethyl
4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octane-1-carboxylate
[0618] Lithium diisopropylamide (2 M in THF, 4.8 mL, 9.60 mmol) was
added dropwise to a solution of ethyl
4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
(1.81 g, 4.72 mmol), HMPA (4.23 g, 23.61 mmol), and THF (90 mL) at
-78.degree. C. The mixture was stirred at -78.degree. C. for 3 h,
added to saturated NH.sub.4Cl (90 mL), and then extracted with
EtOAc (2.times.150 mL). The combined organic layers were washed
(100 mL H.sub.2O and then 100 mL brine), dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified by silica gel
chromatography (petroleum ether/EtOAc=30/1) to give ethyl
4-(4-methoxy-3-methylphenyl)177yridin[2.2.2]octane-1-carboxylate
(1.17 g, 82%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 6.98-7.05 (m, 2H), 6.69 (d, 1H), 4.05 (q, 2H), 3.73 (s,
3H), 2.14 (s, 3H), 1.70-1.87 (m, 12H), 1.18 (t, 3H); LCMS: 303.3
[M+H].sup.+.
Step 8:
(4-(4-Methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methanol
[0619] Diisobutylaluminum hydride (1 M in toluene, 14 mL, 14.0
mmol) was added to a solution of ethyl
4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octane-1-carboxylate
(1.64 g, 5.42 mmol) and CH.sub.2Cl.sub.2 (100 mL) at -78.degree. C.
The mixture was stirred at -78.degree. C. for 1 h, stirred at rt
for 2 h, and then added to ice H.sub.2O (80 mL). The pH was
adjusted (pH=6) with 1 N HCl, and the mixture was filtered. The
layers were separated, and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.200 mL). The combined organic layers were
washed (100 mL water and then 100 mL brine), dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by silica gel chromatography (petroleum ether/EtOAc=10/1)
to give
(4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methanol
(1.22 g, 82%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 6.99-7.07 (m, 2H), 6.64-6.72 (m, 1H), 3.73 (s, 3H), 3.25
(s, 2H), 2.14 (s, 3H), 1.69-1.81 (m, 6H), 1.40-1.50 (m, 6H); LCMS:
261.2 [M+H].sup.+.
Step 9:
4-(4-Methoxy-3-methylphenyl)pyridin[2.2.2]octane-1-carbaldehyde
[0620] Pyridinium chlorochromate (1.03 g, 4.78 mmol) was added to a
mixture of
(4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methanol (621
mg, 2.39 mmol), SiO.sub.2 (1.93 g, 32.19 mmol) and CH.sub.2Cl.sub.2
(120 mL). The mixture was stirred at rt for 2 h, filtered through a
neutral alumina plug and then concentrated to give Intermediate 3
(601 mg, 93%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 9.48-9.56 (s, 1H), 7.06-7.11 (m, 2H), 6.72-6.78 (m, 1H),
3.81 (s, 3H), 2.22 (s, 3H), 1.83-1.91 (m, 6H), 1.71-1.80 (m, 6H);
LCMS: 259.3 [M+H].sup.+.
[0621] The Intermediate below was synthesized from
5-bromo-N,N-dimethylpyridin-2-amine following the procedures
described for Intermediate 5.
TABLE-US-00005 Int Structure Name [M + H].sup.+ 5.01 ##STR00607##
trans-4-(6-(Dimethylamino)pyridine- 3-yl)cyclohexanecarbaldehyde
259.2 Alternate conditions: Step 2: 0.degree. C., overnight; Step
3: K.sub.2OsO.sub.4 2H.sub.2O; Step 7: -78.degree. C., 1 h then rt,
overnight; Step 9: oxalyl chloride, DMSO, Et.sub.3N, -78.degree.
C.
Intermediate 6
3-(2-Cyclopropylthiazol-5-yl)aniline
##STR00608##
[0623] A mixture of 3-aminophenylboronic acid (2.02 g, 14.7 mmol),
Pd(dppf)Cl.sub.2 (363 mg, 0.50 mmol), aqueous K.sub.2CO.sub.3 (2.2
M, 13.5 mL, 29.7 mmol), and dioxane (17.5 mL) was degassed with 3
vacuum/N.sub.2 cycles. 5-Bromo-2-cyclopropylthiazole (2.01 g, 9.85
mmol) was added, and the reaction was heated at 80.degree. C. for
4.25 h. The reaction was allowed to cool to rt and then poured into
100 mL water. The mixture was extracted with 100 mL EtOAc, and the
organics were washed with 75 mL brine. The combined aqueous washes
were back extracted with 50 mL EtOAc. The combined extracts were
dried (Na.sub.2SO.sub.4), filtered, concentrated, and purified by
silica gel chromatography (10-40% EtOAc in hexanes) to give
3-(2-cyclopropylthiazol-5-yl)aniline (1.84 g, 87%) as a yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.79 (s, 1H),
7.04 (t, 1H), 6.76-6.71 (m, 2H), 6.55-6.49 (m, 1H), 5.23 (s, 2H),
2.41-2.33 (m, 1H), 1.14-1.08 (m, 2H), 1.00-0.94 (m, 2H); LCMS:
217.4 [M+H].sup.+.
[0624] The Intermediates below were synthesized from the
appropriate boronic acid and the appropriate heteroaryl bromide
following the procedure described for Intermediate 6.
TABLE-US-00006 Int Structure Name [M + H].sup.+ 6.01 ##STR00609##
3-(2-Methoxythiazol-5-yl)aniline 207.4 6.02.sup.1 ##STR00610##
4-(2-Cyclopropylthiazol-5- yl)pyridin-2-amine 218.0 6.03.sup.2
##STR00611## 3-(2-Isopropylthiazol-5-yl)aniline 219.3 6.04.sup.2
##STR00612## 4-(2-Isopropylthiazol-5-yl)pyridin- 2-amine 220.3
Alternate conditions: .sup.1Cs.sub.2CO.sub.3, dioxane/H.sub.2O
(4:1), 80.degree. C., overnight; .sup.2Heated at 90.degree. C.
Intermediate 7
3-(1-Cyclopropyl-1H-pyrazol-4-yl)aniline
##STR00613##
[0626] A mixture of 3-iodoaniline (63.36 g, 289.9 mmol),
Pd(dppf)Cl.sub.2 (7.05 g, 9.63 mmol), K.sub.2CO.sub.3 (2.2 M, 265
mL, 583.0 mmol), and dioxane (340 mL) was degassed with
vacuum/N.sub.2 cycles (3.times.).
1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(.about.90%, 50.09 g, 192.6 mmol) was added, and the mixture was
heated in a pre-heated oil bath (90.degree. C.) for 20 min
(internal temp at 20 min was 72.degree. C.). The reaction was
allowed to cool to rt, diluted with EtOAc (800 mL) and H.sub.2O
(800 mL), and then filtered through Celite with EtOAc washing
(.about.400 mL). The layers were separated, and the organic layer
was washed (800 mL H.sub.2O), dried (Na.sub.2SO.sub.4), filtered,
and concentrated (73.88 g). The residue was dry loaded onto silica
gel and purified by silica gel chromatography (20-60% EtOAc in
hexanes) to give 3-(1-cyclopropyl-1H-pyrazol-4-yl)aniline (31.5 g,
82%) as a beige solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.03 (s, 1H), 7.66 (d, 1H), 6.97 (t, 1H), 6.73-6.72 (m, 1H),
6.71-6.68 (m, 1H), 6.42-6.38 (m, 1H), 5.00 (s, 2H), 3.75-3.68 (m,
1H), 1.08-1.00 (m, 2H), 1.00-0.92 (m, 2H); LCMS: 200.3
[M+H].sup.+.
[0627] The Intermediates below were synthesized from the
appropriate boronic acid/ester and the appropriate aryl halide
following the procedure described for Intermediate 7.
TABLE-US-00007 Int Structure Name [M + H].sup.+ 7.01.sup.1
##STR00614## 4-(1-Cyclopropyl-1H-pyrazol-4- yl)pyridin-2-amine
201.3 7.02.sup.1 ##STR00615## 4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2-amine 203.0 7.03 ##STR00616##
3-(1-Isopropyl-1H-pyrazol-4- yl)aniline 202.0 7.04 ##STR00617##
3-(1-(tert-Butyl)-1H-pyrazol-4- yl)aniline 216.4 7.05 ##STR00618##
3-(1-Cyclobutyl-1H-pyrazol-4- yl)aniline 214.4 7.06.sup.2
##STR00619## 4-(1-Cyclopropyl-1H-pyrazol-4-
yl)-6-methylpyridin-2-amine 215.1 .sup.14-bromopyridin-2-amine was
used. .sup.24-bromo-6-methylpyridin-2-amine was used.
Intermediate 8
3-(2-Isopropyloxazol-4-yl)aniline
##STR00620##
[0629] Step 1: 2-Isopropyl-4-(3-nitrophenyl)oxazole
[0630] Isobutyramide (44.62 g, 512.2 mmol) was added to a solution
of 2-bromo-1-(3-nitrophenyl)ethanone (50 g, 205 mmol) in toluene
(100 mL) at rt. The mixture was refluxed for 4 h, allowed to cool
to rt, and then filtered through filter paper. The filtrate was
diluted with diethyl ether (80 mL). The organics were successively
washed with H.sub.2O (50 mL), aq. NaOH (0.5 M, 50 mL), aq. HCl (0.5
M, 50 mL), and brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered, concentrated, and then purified by silica gel
chromatography (petroleum ether/EtOAc=1/0 to 10/1) to give
2-isopropyl-4-(3-nitrophenyl)oxazole (28 g, 59%) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.76 (s, 1H), 8.54 (s,
1H), 8.19-8.13 (m, 2H), 7.71 (t, 1H), 3.20-3.09 (m, 1H), 1.33 (d,
6H); LCMS: 233.1 [M+H].sup.+.
Step 2: 3-(2-Isopropyloxazol-4-yl)aniline
[0631] A mixture of palladium on carbon (10 wt. %, 3 g, 2.8 mmol),
2-isopropyl-4-(3-nitrophenyl)oxazole (27 g, 116 mmol), and
CH.sub.3OH (80 mL) was degassed with vacuum/H.sub.2 cycles
(3.times.). The mixture was stirred under H.sub.2 at rt for 4 h and
then filtered through Celite. The filtrate was concentrated and
then purified by silica gel chromatography (petroleum
ether/EtOAc=30/1 to 10/1) to give 3-(2-isopropyloxazol-4-yl)aniline
(15 g, 64%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.77 (s, 1H), 7.19-7.09 (m, 3H), 6.64-6.62 (m, 1H), 3.72
(s, 2H), 3.18-3.11 (m, 1H), 1.38 (d, 6H); LCMS: 203.1
[M+H].sup.+.
[0632] The following Intermediate was synthesized from
cyclopropanecarboxamide following the procedure described for
Intermediate 8.
TABLE-US-00008 Int Structure Name [M + H].sup.+ 8.01 ##STR00621##
3-(2-Cyclopropyl- oxazol-4- yl)aniline 201.1
Intermediate 9
3-Cyclopropyl-5-(3-nitrophenyl)isothiazole
##STR00622##
[0633] Step 1: 1-Cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one
[0634] A mixture of ethynyltrimethylsilane (1.00 g, 10.18 mmol),
cyclopropanecarbonyl chloride (1.06 g, 10.18 mmol), Et3N (1.03 g,
10.18 mmol), CuI (78 mg, 0.407 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2
(143 mg, 0.204 mmol), and THF (20 mL) was degassed with
vacuum/N.sub.2 cycles (3.times.), stirred at rt for 1 h, quenched
with NH.sub.4Cl (20 mL), and then extracted with EtOAc (3.times.20
m). The combined organic layers were washed (2.times.25 mL brine),
dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue
was purified by silica gel chromatography (petroleum
ether/EtOAc=50/1) to give
1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one (350 mg, 21%) as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
81.76-1.89 (m, 1H), 0.95-1.10 (m, 2H), 0.79-0.82 (m, 2H), 0.00 (s,
9H); LCMS: 167.1 [M+H].sup.+.
Step 2: 1-Cyclopropyl-3-(3-nitrophenyl)prop-2-yn-1-one
[0635] A mixture of 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one
(50 mg, 0.301 mmol), 1-iodo-3-nitrobenzene (115 mg, 0.460 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (27 mg, 0.039 mmol), PPh.sub.3 (21 mg,
0.081 mmol), Et.sub.3N (107.4 mg, 1.06 mmol), CuI (4 mg, 0.021
mmol), and DMF (4 mL) was degassed with vacuum/N.sub.2 cycles
(3.times.) and heated to 60.degree. C. TBAF (1 M, 300 uL, 0.3 mmol)
was added over 30 minutes to the mixture, and the reaction was
stirred at 60.degree. C. for 3 h. The solution was concentrated and
purified by silica gel chromatography (petroleum ether/EtOAc=20/1
to 5/1) to give 1-cyclopropyl-3-(3-nitrophenyl)prop-2-yn-1-one (40
mg, 62%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.38-8.47 (m, 1H), 8.26-8.35 (m, 1H), 7.82-7.91 (m, 1H),
7.56-7.66 (m, 1H), 2.18-2.27 (m, 1H), 1.33-1.38 (m, 2H), 1.15-1.19
(m, 2H).
Step 3: 1-Cyclopropyl-3-(3-nitrophenyl)prop-2-yn-1-one
[0636] A mixture of 1-cyclopropyl-3-(3-nitrophenyl)prop-2-yn-1-one
(800 mg, 3.72 mmol), NHSCN (314 mg, 4.13 mmol), and
2-methoxy-2-methylpropane (10 mL) was degassed with vacuum/N.sub.2
cycles (3.times.), stirred at 60.degree. C. overnight, and quenched
with H.sub.2O (10 mL). The layers were separated, and the aqueous
phase was extracted with 2-methoxy-2-methylpropane (10 mL). The
combined organic extracts were washed (5 mL H.sub.2O), dried
(K.sub.2CO.sub.3), filtered, and concentrated. The crude
(Z)-1-cyclopropyl-3-(3-nitrophenyl)-3-thiocyanatoprop-2-en-1-one
(800 mg) was used in the next step without further purification.
LCMS: 248.0 [M-CN].sup.+.
Step 4: 3-Cyclopropyl-5-(3-nitrophenyl)isothiazole
[0637] A mixture of
(Z)-1-cyclopropyl-3-(3-nitrophenyl)-3-thiocyanatoprop-2-en-1-one
(800 mg, 2.92 mmol) and NH.sub.3 (50 mL) at -78.degree. C. was
allowed to slowly warm to rt over 2 h. The residue was purified by
silica gel chromatography (petroleum ether/EtOAc=5/1) to give
3-cyclopropyl-5-(3-nitrophenyl)isothiazole (200 mg, 28%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.35 (s, 1H),
8.17 (d, 1H), 7.80 (d, 1H), 7.55 (t, 1H), 7.15 (s, 1H), 2.08-2.22
(m, 1H), 0.95-1.01 (m, 4H); LCMS: 247.1 [M+H].sup.+.
Step 6: 3-(3-Cyclopropylisothiazol-5-yl)aniline
[0638] A mixture of 3-cyclopropyl-5-(3-nitrophenyl)isothiazole (300
mg, 1.22 mmol), SnCl.sub.2.2H.sub.2O (1.10 g, 4.87 mmol), EtOH (5
mL), and H.sub.2O (500 uL) was degassed with vacuum/N.sub.2 cycles
(3.times.), stirred at 78.degree. C. for 2 h, poured into
CH.sub.2Cl.sub.2 (10 mL), and then filtered. The filtrate was
diluted with H.sub.2O (10 mL), extracted with CH.sub.2Cl.sub.2
(3.times.10 mL), washed (15 mL brine), concentrated, and then
purified by silica gel chromatography (petroleum ether/EtOAc=5/1)
to give 3-(3-cyclopropylisothiazol-5-yl)aniline (140 mg, 53%) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.20 (t,
1H), 7.06 (s, 1H), 6.98 (d, 1H), 6.87 (t, 1H), 6.68-6.73 (m, 1H),
3.78 (s, 2H), 2.11-2.27 (m, 1H), 0.93-1.14 (m, 4H); LCMS: 217.2
[M+H].sup.+.
Intermediate 10
4-(2-Cyclopropyloxazol-4-yl)pyridine-2-amine
##STR00623##
[0639] Step 1: 2-Bromo-1-(2-chloropyridin-4-yl)ethanone
[0640] Bromine (12.94 g, 80.99 mmol) and HBr (19.5 mL, 108.0 mmol,
30% in AcOH) were added to a mixture of
1-(2-chloropyridin-4-yl)ethanone (14 g, 90 mmol) and AcOH (280 mL)
at rt. The mixture was stirred at rt overnight, diluted with MTBE
(400 mL), and filtered. The filter cake was washed (400 mL MTBE),
added to a mixture of saturated NaHCO.sub.3 (300 mL) and EtOAc (500
mL), and then stirred for 1 h. The organic layer was separated and
washed (300 mL saturated NaHCO.sub.3). The combined aqueous layers
were extracted with EtOAc (2.times.300 mL). The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated to
give 2-bromo-1-(2-chloropyridin-4-yl)ethanone (15 g, crude) as a
red solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (d, 1H),
7.80 (s, 1H), 7.70 (d, 1H), 4.40 (s, 2H); LCMS 234.0
[M+H].sup.+.
Step 2: 4-(2-Chloropyridin-4-yl)-2-cyclopropyloxazole
[0641] A mixture of 2-bromo-1-(2-chloropyridin-4-yl)ethanone (20 g,
85 mmol), cyclopropanecarboxamide (9.07 g, 106 mmol), AgOTf (43.83
g, 170.6 mmol), and EtOAc (300 mL) was stirred at 70.degree. C.
overnight in darkness under N.sub.2 and then allowed to cool to rt.
Brine (300 mL) was added to the mixture, and the mixture was
stirred for 3 h and filtered. The aqueous layer was separated and
extracted with EtOAc (3.times.300 mL). The combined organic layers
were washed (2.times.300 mL saturated NaHCO.sub.3 and then 200 mL
brine), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
residue was purified by silica gel chromatography (petroleum
ether/EtOAc=9/1) to give
4-(2-chloropyridin-4-yl)-2-cyclopropyloxazole (13.2 g, 70%) as a
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.38 (d,
1H), 7.92 (s, 1H), 7.66 (d, 1H), 7.49 (d, 1H), 2.17-2.09 (m, 1H),
1.18-1.07 (m, 4H); LCMS 220.9 [M+H].sup.+.
Step 3: 4-(2-Cyclopropyloxazol-4-yl)pyridin-2-amine
[0642] Lithium bis(trimethylsilyl)amide (126 mL, 126 mmol, 1 M in
THF) was added to a mixture of
4-(2-chloro-4-pyridyl)-2-cyclopropyl-oxazole (13.2 g, 59.8 mmol),
XPhos (2.28 g, 4.80 mmol), Pd.sub.2(dba).sub.3 (2.19 g, 2.394
mmol), and THF (150 mL) at rt under N.sub.2. The reaction mixture
was heated at 60.degree. C. overnight, allowed to cool to rt, added
to ice-cold HCl (200 mL, 1 M), and then stirred for 2 h. Sodium
hydroxide (1 M) was added to the mixture (pH=11), and the mixture
was extracted with EtOAc (3.times.300 mL). The combined organic
layers were washed (200 mL brine), dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified by silica gel
chromatography (petroleum ether/EtOAc/EtOH=36/3/1) and then
triturated (petroleum ether/EtOAc/EtOH=36/3/1) to give
4-(2-cyclopropyloxazol-4-yl)pyridine-2-amine (3.53 g, 29%) as a
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.46 (s,
1H), 7.88 (d, 1H), 6.80 (s, 1H), 6.77 (d, 1H), 5.96 (s, 2H),
2.25-2.05 (m, 1H), 1.09-1.03 (m, 2H), 1.02-0.96 (m, 2H); LCMS 202.1
[M+H].sup.+.
[0643] The following Intermediate was synthesized from
isobutyramide following the procedure described for Intermediate
10.
TABLE-US-00009 Int Structure Name [M + H].sup.+ 10.01 ##STR00624##
4-(2-Isopropyl- oxazol-4- yl)pyridine-2- amine 204.2
Intermediate 11
4-(2-Ethyloxazol-4-yl)pyridin-2-amine
##STR00625##
[0644] Step 1: 2-Chloroisonicotinoyl chloride
[0645] Oxalyl chloride (96.67 g, 761.64 mmol) was added to a
solution of 2-chloropyridine-4-carboxylic acid (75 g, 476.03 mmol),
DMF (3.48 g, 47.60 mmol), and CH.sub.2Cl.sub.2 (850 mL) at
0.degree. C. under N.sub.2. The reaction was stirred at rt for 2.5
h and then concentrated to dryness to give 2-chloroisonicotinoyl
chloride (85 g, crude) as a black brown oil.
Step 2: 1-(2-Chloropyridin-4-yl)-2-diazoethanone
[0646] A suspension of 2-chloropyridine-4-carbonyl chloride (85 g,
crude) in CH.sub.3CN (50 mL) and THF (50 mL) was added to a
solution of diazomethyl(trimethyl)silane (2 M in n-hexane, hexane,
483 mL, 966 mmol), CH.sub.3CN (400 mL), and THF (400 mL) at
0.degree. C. under N.sub.2. The reaction was stirred at rt for 1 h
and then concentrated to dryness to give
1-(2-chloropyridin-4-yl)-2-diazoethanone (90 g, crude) as a black
brown oil. LCMS: 182.2 [M+H].sup.+.
Step 3: 2-Chloro-1-(2-chloropyridin-4-yl)ethanone
[0647] Hydrochloric acid (12 M, 85.4 mL, 1025 mmols) was added to a
solution of 1-(2-chloro-4-pyridyl)-2-diazo-ethanone (60 g, crude),
THF (200 mL), and CH.sub.3CN (200 mL) at 0.degree. C. under
N.sub.2. The reaction was stirred at rt for 30 min, quenched with
NaHCO.sub.3 (100 g), and then filtered. The filtrate was diluted
with H.sub.2O (1000 mL) and extracted with EtOAc (2.times.250 mL).
The combined organic layers were washed with water (2.times.150
mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
residue was purified by silica gel chromatography (petroleum
ether/EtOAc=20/1) to give 2-chloro-1-(2-chloropyridin-4-yl)ethanone
(36 g) as a green solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.63 (d, 1H), 7.78 (s, 1H), 7.67 (d, 1H), 4.65 (s, 2H); LCMS: 189.8
[M+H].sup.+.
Step 4: 4-(2-Chloropyridin-4-yl)-2-ethyloxazole
[0648] Silver trifluoromethanesulfonate (59.5 g, 231.55 mmol) was
added to a solution of 2-chloro-1-(2-chloropyridin-4-yl)ethanone
(22 g, 115.77 mmol), propanamide (11.00 g, 150.51 mmol), and
dioxane (250 mL) at rt under N.sub.2. The mixture was refluxed
overnight in the dark, allowed to cool to rt, poured into a mixture
of saturated NaHCO.sub.3 (800 mL) and EtOAc (1000 mL), and then
filtered. The filtrate was extracted with EtOAc (2.times.1000 mL),
and the combined organic phase was washed (800 mL brine), dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel chromatography (petroleum ether/EtOAc=3/1 to
give 4-(2-chloropyridin-4-yl)-2-ethyloxazole (15.1 g, 60%) as a
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.31 (d,
1H), 7.92 (s, 1H), 7.60 (s, 1H), 7.53-7.37 (m, 1H), 2.79(q, 2H),
1.32 (t, 3H); LCMS: 209.1 [M+H].sup.+.
Step 5: 4-(2-Ethyloxazol-4-yl)pyridin-2-amine
[0649] Lithium bis(trimethylsilyl)amide (1 M in THF, 76 mL, 76
mmol) was added to a solution of
4-(2-chloropyridin-4-yl)-2-ethyloxazole (16 g, 76.69 mmol), XPhos
(3.66 g, 7.67 mmol), Pd.sub.2(dba).sub.3 (3.51 g, 3.83 mmol), and
dioxane (320 mL) at rt. The mixture was heated to 100.degree. C.
under N.sub.2 for 2 h, allowed to cool to rt, poured into water
(500 mL), and then extracted with EtOAc (2.times.600 mL). The
combined organic layers were washed (300 mL brine), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by silica gel chromatography (petroleum
ether/EtOAc=3/1-1/1) and then triturated (100 mL 1:1 petroleum
ether: MTBE) to give 4-(2-ethyloxazol-4-yl)pyridin-2-amine (8.02 g,
55%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.51 (s, 1H), 7.87 (d, 1H), 6.82 (s, 1H), 6.77 (d, 1H),
5.95 (s, 2H), 2.78 (q, 2H), 1.25 (t, 3H); LCMS: 190.1
[M+H].sup.+.
Intermediate 12
5-(3-Aminophenyl)-N,N-dimethylpyridin-2-amine
##STR00626##
[0651] A mixture of 3-iodoaniline (3.96 g, 18.08 mmol),
(6-(dimethylamino)pyridine-3-yl)boronic acid (2.04 g, 12.26 mmol),
2.2 M K.sub.2CO.sub.3 (16 mL, 35 mmol), Pd(dppf)Cl.sub.2 (443 mg,
0.61 mmol), and dioxane (21 mL) was degassed with vacuum/nitrogen
cycles (3.times.), heated at 90.degree. C. for 60 min, and then
cooled to rt. The reaction was diluted with EtOAc (100 mL), washed
(2.times.100 mL H.sub.2O and then 100 mL brine), dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
silica gel chromatography (20-50% EtOAc in hexanes) to give
5-(3-aminophenyl)-N,N-dimethylpyridin-2-amine as a beige solid
(2.18 g, 84%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.30
(d, 1H), 7.68 (dd, 1H), 7.05 (t, 1H), 6.75 (t, 1H), 6.72-6.66 (m,
2H), 6.49 (dd, 1H), 5.08 (s, 2H), 3.04 (s, 6H); LCMS: 214.4
[M+H].sup.+.
Intermediate 13
3-Iodo-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)aniline
##STR00627##
[0653] Sodium triacetoxyborohydride (3.74 g, 17.6 mmol) was added
to a solution of Intermediate 3 (2.56 g, 11.0 mmol), 3-iodoaniline
(2.56 g, 11.7 mmol), acetic acid (1.3 mL, 23 mmol) and
dichloroethane (45 mL) at rt under Na. The reaction was stirred for
80 min, poured into 50 mL sat'd NaHCO.sub.3 and extracted with 50
mL EtOAc. The EtOAc layer was washed with 50 mL sat'd NaHCO.sub.3
and washed with 50 mL brine. The aqueous layers were combined and
back extracted with 25 mL EtOAc. The combined organics were dried
(Na.sub.2SO.sub.4), filtered, concentrated and purified by silica
gel chromatography (0-5% EtOAc in hexanes) to give
3-iodo-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)aniline
(4.43 g, 88%) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.01-6.95 (m, 2H), 6.91 (s, 1H), 6.86-6.77 (m, 3H), 6.57
(d, 1H), 5.92 (t, 1H), 3.73 (s, 3H), 2.85 (t, 2H), 2.42-2.31 (m,
1H), 2.11 (s, 3H), 1.94-1.85 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.50
(m, 1H), 1.45-1.31 (m, 2H), 1.14-1.00 (m, 2H); LCMS: 436.4
[M+H].sup.+.
Intermediate 14
3-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo
[2.2.2]octan-1-yl)methyl)aniline
##STR00628##
[0655] Dichloroethane was cooled in an ice/water bath under
N.sub.2. Intermediate 5 (151 mg, 0.58 mmol), Intermediate 7 (118
mg, 0.59 mmol), and then sodium triacetoxyborohydride (198 mg, 0.93
mmol) were added to the reaction at 0.degree. C. The reaction was
allowed to warm to rt, stirred at rt for 85 min, poured into 20 mL
saturated NaHCO.sub.3, and then extracted with 20 mL EtOAc. The
organic layer was washed with 20 mL brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and purified by silica
gel chromatography (10-30% EtOAc in hexanes) to give
3-(1-cyclopropyl-1H-pyrazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo-
[2.2.2]octan-1-yl)methyl)aniline (233 mg, 90%) as a white foam.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.09 (s, 1H), 7.71 (s,
1H), 7.11-7.05 (m, 2H), 7.00 (t, 1H), 6.84-6.76 (m, 2H), 6.68 (d,
1H), 6.47 (d, 1H), 5.32 (t, 1H), 3.75-3.68 (m, 4H), 2.83 (d, 2H),
2.12 (s, 3H), 1.78-1.69 (m, 6H), 1.62-1.52 (m, 6H), 1.10-1.04 (m,
2H), 1.00-0.93 (m, 2H); LCMS: 442.3 [M+H].sup.+.
[0656] The Intermediates below were synthesized from the
appropriate amine (SM or Intermediate) and the appropriate aldehyde
Intermediate following the procedures described for Intermediate
14.
TABLE-US-00010 Int Structure Name [M + H].sup.+ 14.01.sup.1
##STR00629## 5-(trans-4-(((3- Iodophenyl)amino)methyl)cyclohexyl)-
2-methoxybenzonitrile 447.1 14.02.sup.1 ##STR00630##
4-Bromo-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)pyridin- 2-amine 389.1 14.03
##STR00631## 3-Iodo-N-((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)aniline 462.0 14.04
##STR00632## 4-Bromo-N-((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)pyridin-2-amine 415.2
14.05 ##STR00633## N-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-3-(2- methoxythiazol-5-yl)aniline
423.2 14.06 ##STR00634## 3-(2-Cyclopropylthiazol-5-yl)-N-((trans-
4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)aniline 433.3 14.07
##STR00635## N-((tans-4-(3-Chloro-4-
methoxyphenyl)cyclohexyl)methyl)-3-
(2-cyclopropylthiazol-5-yl)aniline 453.3 14.08 ##STR00636##
5-(trans-4-(((3-(2-Cyclopropylthiazol-5-
yl)phenyl)amino)methyl)cyclohexyl)- N,N-dimethylpyridin-2-amine
433.4 14.09 ##STR00637## 3-(2-Cyclopropylthiazol-5-yl)-N-((trans-
4-(3-fluoro-1-methyl-1H-indazol-5- yl)cyclohexyl)methyl)aniline
461.2 14.10 ##STR00638## 5-(trans-4-(((3-(2-Cyclopropylthiazol-5-
yl)phenyl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile 444.3
14.11.sup.2 ##STR00639## 5-(trans-4-(((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2- yl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile
445.9 14.12 ##STR00640## 6-(trans-4-(((3-(2-Cyclopropylthiazol-5-
yl)phenyl)amino)methyl)cyclohexyl)-3- methoxypicolinonitrile 445.3
14.13.sup.2 ##STR00641## 6-(trans-4-(((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2- yl)amino)methyl)cyclohexyl)-3- methoxypicolinonitrile
446.6 14.14 ##STR00642## 3-(2-Cyclopropylthiazol-5-yl)-N-((trans-
4-(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)aniline 434.1
14.15 ##STR00643## 4-(2-Cyclopropylthiazol-5-yl)-N-((trans-
4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)pyridin- 2-amine
434.3 14.16 ##STR00644## 4-(2-Cyclopropylthiazol-5-yl)-N-((trans-
4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)pyridin-2-amine 435.3 14.17 ##STR00645##
3-(2-Isopropylthiazol-5-yl)-N-((trans-4-
(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)aniline 436.2
14.18.sup.2 ##STR00646## 4-(2-Isopropylthiazol-5-yl)-N-((trans-4-
(4-methoxy-3- methylphenyl)cyclohexyl)methyl)pyridin- 2-amine 436.6
14.19.sup.1 ##STR00647## 4-(2-Isopropylthiazol-5-yl)-N-((tarns-4-
(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)pyridin-2-amine
437.5 14.20 ##STR00648## 3-(2-Cyclopropylthiazol-5-yl)-N-((4-(4-
methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)aniline
459.3 14.21 ##STR00649## 5-(4-(((3-(2-Cyclopropylthiazol-5-
yl)phenyl)amino)methyl)bicyclo[2.2.2]
octan-1-yl)-N,N-dimethylpyridin-2-amine 459.4 14.22 ##STR00650##
3-(1-(Cyclopropyl-1H-pyrazol-4-yl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)aniline 416.3 14.23 ##STR00651##
N-((trans-4-(3-Chloro-4- methoxyphenyl)cyclohexyl)methyl)-3-
(1-cyclopropyl-1H-pyrazol-4-yl)aniline 436.6 14.24 ##STR00652##
5-(trans-4-(((3-(1-Cyclopropyl-1H- pyrazol-4-
yl)phenyl)amino)methyl)cyclohexyl)- N,N-dimethylpyridin-2-amine
416.3 14.25 ##STR00653## 3-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-
((trans-4-(3-fluoro-1-methyl-1H-
indazol-5-yl)cyclohexyl)methyl)aniline 444.6 14.26 ##STR00654##
4-(1-Cyclopropyl-1H-pyrazol-4-yl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)pyridin- 2-amine 417.1 14.27.sup.3
##STR00655## 4-(1-Cyclopropyl-1H-pyraozl-4-yl)-N-
((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-6-
methylpyridin-2-amine 431.6 14.28 ##STR00656##
3-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)aniline 417.1 14.29 ##STR00657##
4-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)pyridin-2-amine 418.3 14.30 ##STR00658##
3-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-
((trans-4-(6-methoxy-5-methylpyridin-
3-yl)cyclohexyl)methyl)aniline 417.3 14.31 ##STR00659##
N-((trans-4-(5-Chloro-6- methoxypyridin-3-
yl)cyclohexyl)methyl)-3-(1-cyclopropyl- 1H-pyrazol-4-yl)aniline
437.4 14.32 ##STR00660## 5-(trans-4-(((3-(1-Cyclopropyl-1H-
pyrazol-4- yl)phenyl)amino)methyl)cyclohexyl)-2-
methoxybenzonitrile 427.3 14.33 ##STR00661##
5-(trans-4-(((4-(1-Cyclopropyl-1H- pyrazol-4-yl)pyridin-2-
yl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile 428.3 14.34
##STR00662## 6-(trans-4-(((3-(1-Cyclopropyl-1H- pyrazol-4-
yl)phenyl)amino)methyl)cyclohexyl)-3- methoxypicolinonitrile 428.3
14.35 ##STR00663## 6-(trans-4-(((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2- yl)amino)methyl)cyclohexyl)-3-
methoxypicolinonitrile 429.4 14.36 ##STR00664##
4-(1-Cyclopropyl-1H-pyrazol-4-yl)-N- ((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)pyridin-2-amine 443.1
14.37 ##STR00665## 5-(4-(((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)amino)methyl)bicyclo[2.2.2]
octan-1-yl)-N,N-dimethylpyridin-2-amine 442.4 14.38 ##STR00666##
3-(1-Isopropyl-1H-pyrazol-4-yl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)aniline 418.3 14.39 ##STR00667##
4-(1-Isopropyl-1H-pyrazol-4-yl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)pyridin- 2-amine 419.3 14.40
##STR00668## 3-(1-Isopropyl-1H-pyrazol-4-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)aniline 419.7 14.41.sup.3 ##STR00669##
4-(1-Isopropyl-1H-pyrazol-4-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)pyridin-2-amine 420.3 14.42 ##STR00670##
5-(trans-4-(((4-(1-Isopropyl-1H- pyrazol-4-yl)pyridin-2-
yl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile 430.4
14.43.sup.2,3,4 ##STR00671## 5-(4-(((4-(1-Isopropyl-1H-pyrazol-4-
yl)pyridin-2- yl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile
430.3 14.44.sup.2 ##STR00672## 6-(trans-4-(((3-(1-Isopropyl-1H-
pyrazol-4- yl)phenyl)amino)methyl)cyclohexyl)-3-
methoxypicolinonitrile 430.4 14.45 ##STR00673##
6-(trans-4-(((4-(1-Isopropyl-1H- pyrazol-4-yl)pyridin-2-
yl)amino)methyl)cyclohexyl)-3- methoxypicolinonitrile 431.4 14.46
##STR00674## 3-(1-(tert-Butyl)-1H-pyrazol-4-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)aniline 433.4 14.47 ##STR00675##
3-(1-Cyclobutyl-1H-pyrazol-4-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-
2-yl)cyclohexyl)methyl)aniline 431.8 14.48 ##STR00676##
3-(2-Cyclopropyloxazol-4-yl)-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)aniline 417.3 14.49.sup.2
##STR00677## 4-(2-Cyclopropyloxazol-4-yl)-N-((trans-
4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl) pyridin-2-amine
418.6 14.50.sup.3 ##STR00678##
4-(2-Cyclopropyloxazol-4-yl)-N-((trans-
4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)pyridin-2-amine 419.5 14.51 ##STR00679##
5-(4-(((3-(2-Cyclopropyloxazol-4-
yl)phenyl)amino)methyl)bicyclo[2.2.2]
octan-1-yl)-N,N-dimethylpyridin-2-amine 443.3 14.52.sup.2
##STR00680## 5-(trans-4-(((4-(2-Cyclopropyloxazol-4- yl)pyridin-2-
yl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile 429.3
14.53.sup.2 ##STR00681## 5-(trans-4-(((4-(2-Isopropyloxazol-4-
yl)pyridin-2- yl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile
431.4 14.54.sup.2 ##STR00682##
6-(trans-4-(((4-(2-Cyclopropyloxazol-4- yl)pyridin-2-
yl)amino)methyl)cyclohexyl)-3- methoxypicolinonitrile 430.4
14.55.sup.3 ##STR00683## 4-(2-Ethyloxazol-4-yl)-N-((trans-4-(5-
methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)pyridin-2-amine
407.4 Alternate conditions: .sup.1Utilized procedure for
Intermediate 13; .sup.2Heated at 40.degree. C. .sup.3Solvent was
CH.sub.2Cl.sub.2; .sup.4Synthesized from an isomeric mixture of
Intermediate 3.05.
Intermediate 15
trans-4-(Cyanomethyl)cyclohexanecarboxylic acid
##STR00684##
[0657] Step 1: trans-Ethyl
4-((tosyloxy)methyl)cyclohexanecarboxylate
[0658] p-Toluenesulfonyl chloride (1.54 g, 8.05 mmol) was added to
a solution of trans-ethyl 4-(hydroxymethyl)cyclohexanecarboxylate
(1 g, 5.37 mmol), Et.sub.3N (1.63 g, 16.11 mmol), DMAP (131.19 mg,
1.07 mmol) and CH.sub.2Cl.sub.2 (60 mL) at 0.degree. C. The mixture
was allowed to warm to rt overnight. Water (10 mL) was added, and
the layers were separated. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (20 mL). The organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and then purified by
chromatography on silica gel (petroleum ether/EtOAc=20/1) to give
trans-ethyl 4-((tosyloxy)methyl)cyclohexanecarboxylate (1.49 g,
82%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.80 (d, 2H), 7.37 (d, 2H), 4.19-4.06 (m, 2H), 3.85 (d, 2H), 2.47
(s, 3H), 2.20 (t, 1H), 2.05-1.96 (m, 2H), 1.86-1.77 (m, 2H),
1.73-1.61 (m, 1H), 1.43-1.39 (m, 2H), 1.27 (t, 3H), 1.08-0.91 (m,
2H); LCMS: 341.2 [M+H].sup.+.
Step 2: trans-Ethyl 4-(cyanomethyl)cyclohexanecarboxylate
[0659] Potassium cyanide (903.8 mg, 13.88 mmol) was added to a
solution of trans-ethyl 4-((tosyloxy)methyl)cyclohexanecarboxylate
(1.89 g, 5.55 mmol) in DMSO (30 mL) at rt. The mixture was heated
to 50.degree. C. overnight. Water (50 mL) was added, and then the
mixture was extracted with EtOAc (2.times.100 mL). The organic
layers were combined, washed with water (50 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated and then purified by
chromatography on silica gel (petroleum ether/EtOAc=10/1) to give
trans-ethyl 4-(cyanomethyl)cyclohexanecarboxylate (807 mg, 74.45%)
as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 4.05
(q, 2H), 2.27-2.09 (m, 3H), 2.04-1.93 (m, 2H), 1.91-1.80 (m, 2H),
1.68-1.55 (m, 1H), 1.46-1.32 (m, 2H), 1.18 (t, 3H), 1.14-1.00 (m,
2H).
Step 3: trans-4-(Cyanomethyl)cyclohexanecarboxylic acid
[0660] Lithium hydroxide monohydrate (2.60 g, 62.00 mmol) was added
to a solution of trans-ethyl 4-(cyanomethyl)cyclohexanecarboxylate
(807 mg, 4.13 mmol), THF (15 mL) and H.sub.2O (15 mL) at rt. The
mixture was stirred at rt overnight, and then the organic layer was
removed. The aqueous layer was adjusted to pH=1 with 1N HCl and
extracted with CH.sub.2Cl.sub.2 (5.times.20 mL). The organic layers
were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated
to give trans-4-(cyanomethyl)cyclohexanecarboxylic acid (500 mg,
crude) as a yellow oil. .sup.1H NMR (400 MHz,CDCl.sub.3): .delta.
2.37-2.22 (m, 3H), 2.12-2.06 (m, 2H), 2.00-1.91 (m, 2H), 1.75-1.63
(m, 1H), 1.50-1.45 (m, 2H), 1.24-1.09 (m, 2H).
Intermediate 16
tert-Butyl 2-(trans-4-(chlorocarbonyl)cyclohexyl)acetate
##STR00685##
[0661] Step 1: trans-Methyl
4-(chlorocarbonyl)cyclohexanecarboxylate
[0662] Oxalyl chloride (47.72 g, 375.9 mmol) was added dropwise to
a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid
(35 g, 188 mmol) and DMF (1.37 g, 18.8 mmol), and CH.sub.2Cl.sub.2
(700 mL) at rt. The mixture was stirred for 2 h and concentrated to
dryness to give trans-methyl
4-(chlorocarbonyl)cyclohexanecarboxylate (38.5 g, crude) as a
yellow oil.
Step 2: trans-Methyl 4-(2-diazoacetyl)cyclohexanecarboxylate
[0663] (Trimethylsilyl)diazomethane (2 M in hexanes, 385 mL, 770
mmol) was added to a solution of trans-methyl
4-(chlorocarbonyl)cyclohexanecarboxylate (38.5 g, 188.1 mmol),
CH.sub.3CN (700 mL), and THF (700 mL) at 0.degree. C. The reaction
was allowed to warm to rt, stirred overnight, concentrated, and
then dissolved in EtOAc (1000 mL). The organic phase was washed
with water (300 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The residue was purified by silica gel chromatography
(petroleum ether/EtOAc=40/1) to give trans-methyl
4-(2-diazoacetyl)cyclohexanecarboxylate (35 g, 166 mmol, 89%) as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 5.27 (s,
1H), 3.66 (s, 3H), 2.33-2.12 (m, 2H), 2.11-2.00 (m, 2H), 1.98-1.85
(m, 2H), 1.53-1.35 (m, 4H).
Step 3: trans-Methyl
4-(2-(tert-butoxy)-2-oxoethyl)cyclohexanecarboxylate
[0664] Silver benzoate (8.17 g, 35.7 mmol) was added to a solution
of methyl 4-(2-diazoacetyl)cyclohexanecarboxylate (25 g, 119 mmol),
dioxane (300 mL), and tert-BuOH (300 mL) at rt under N.sub.2. The
mixture was stirred for 15 h, poured into water (500 mL), filtered,
and extracted with EtOAc (2.times.1000 mL). The combined organic
layers were washed with water (2.times.300 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by silica gel chromatography (petroleum ether/EtOAc=40/1)
to give trans-methyl
4-(2-(tert-butoxy)-2-oxoethyl)cyclohexanecarboxylate (21.43 g, 67%)
as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 3.65
(s, 3H), 2.28-2.13 (m, 1H), 2.09 (d, 2H), 1.97 (d, 2H), 1.87-1.78
(m, 2H), 1.75-1.66 (m, 1H), 1.55-1.43 (d, 11H), 1.07-0.90 (m,
2H).
Step 4: trans-4-(2-(tert-Butoxy)-2-oxoethyl)cyclohexanecarboxylic
acid
[0665] Lithium hydroxide monohydrate (65.48 g, 1.56 mol) was added
to a solution of methyl
4-(2-tert-butoxy-2-oxo-ethyl)cyclohexanecarboxylate (20 g, 78
mmol), THF (400 mL), and water (400 mL) at rt. The mixture was
stirred overnight and concentrated to remove organic solvent.
Hydrochloric acid (3 M) was added to the mixture (pH=4), and the
resulting precipitate was collected by filtration and dried under
vacuum to give
trans-4-(2-(tert-butoxy)-2-oxoethyl)cyclohexanecarboxylic acid (7.2
g, crude) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 2.29-2.21 (m, 1H), 2.10 (d, 2H), 2.0-1.97 (m, 2H),
1.87-1.80 (m, 2H), 1.78-1.66 (m, 1H), 1.53-1.39 (m, 11H), 1.05-0.95
(m, 2H).
Intermediate 17
trans-4-(3-(tert-Butoxy)-3-oxopropyl)cyclohexanecarboxylic acid
##STR00686##
[0666] Step 1: 2-(trans-4-(Methoxycarbonyl)cyclohexyl)acetic
acid
[0667] A mixture of Intermediate 16, Step 3 (2 g, 7.80 mmol) and
hydrochloric acid (4 M in dioxane, 50 mL) was stirred at rt for 1
h. The mixture was concentrated to dryness to give
2-(trans-4-(methoxycarbonyl)cyclohexyl)acetic acid (1.56 g, crude)
as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 3.67
(s, 3H), 2.32-2.19 (m, 3H), 2.05-1.95 (m, 2H), 1.93-1.84 (m, 2H),
1.84-1.72 (m, 1H), 1.55-1.39 (m, 2H), 1.11-0.97 (m, 2H).
Step 2: trans-Methyl
4-(2-chloro-2-oxoethyl)cyclohexanecarboxylate
[0668] Oxalyl chloride (1.98 g, 15.58 mmol) was added to a solution
of 2-(trans-4-(methoxycarbonyl)cyclohexyl)acetic acid (1.56 g, 7.79
mmol), DMF (57.0 mg, 0.779 mmol), and CH.sub.2Cl.sub.2 (20 mL) at
rt. The mixture was stirred at rt for 2 h and then concentrated to
dryness to give trans-methyl
4-(2-chloro-2-oxoethyl)cyclohexanecarboxylate (1.7 g, crude) as a
yellow oil.
Step 3: trans-Methyl
4-(3-diazo-2-oxopropyl)cyclohexanecarboxylate
[0669] (Trimethylsilyl)diazomethane (2 M in hexanes, 11.6 mL) was
added to a solution of trans-methyl
4-(2-chloro-2-oxoethyl)cyclohexanecarboxylate (1.7 g, 7.77 mmol),
CH.sub.3CN (10 mL), and THF (10 mL) at 0.degree. C. The mixture was
allowed to warm to rt overnight, concentrated to dryness, and then
purified by silica gel chromatography (petroleum ether/EtOAc=10/1)
to give trans-methyl 4-(3-diazo-2-oxopropyl)cyclohexanecarboxylate
(1.2 g, 62%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 5.06 (s, 1H), 3.50 (s, 3H), 2.14-1.99 (m, 3H), 1.88-1.78
(m, 2H), 1.73-1.58 (m, 3H), 1.32-1.29 (m, 2H), 0.93-0.75 (m,
2H).
Step 4: trans-Methyl
4-(3-(tert-butoxy)-3-oxopropyl)cyclohexanecarboxylate
[0670] Silver benzoate (367.5 mg, 1.61 mmol) was added to a
solution of trans-methyl
4-(3-diazo-2-oxopropyl)cyclohexanecarboxylate (1.2 g, 5.35 mmol),
dioxane (10 mL), and t-BuOH (10 mL) at rt. The mixture was stirred
at rt overnight, poured into water (50 mL), and then filtered. The
filtrate was extracted with EtOAc (2.times.50 mL). The organic
layers were combined, washed with water (30 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated, and then purified by
silica gel chromatography (petroleum ether/EtOAc=40/1) to give
trans-methyl 4-(3-(tert-butoxy)-3-oxopropyl)cyclohexanecarboxylate
(730 mg, 50%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 3.59 (s, 3H), 2.22-2.09 (m, 3H), 1.95-1.85 (m, 2H),
1.79-1.69 (m, 2H), 1.48-1.25 (m, 13H), 1.22-1.10 (m, 1H), 0.94-0.78
(m, 2H).
Step 5: trans-4-(3-(tert-Butoxy)-3-oxopropyl)cyclohexanecarboxylic
acid
[0671] Lithium hydroxide monohydrate (113.3 mg, 2.70 mmol) was
added to a solution of trans-methyl
4-(3-(tert-butoxy)-3-oxopropyl)cyclohexanecarboxylate (730 mg, 2.70
mmol), THF (10 mL), and H.sub.2O (10 mL). The mixture was stirred
at 30.degree. C. overnight, concentrated to remove THF, adjusted to
pH=5 with 3 M HCl, and then filtered. The cake was dried under
vacuum to give
trans-4-(3-(tert-butoxy)-3-oxopropyl)cyclohexanecarboxylic acid
(330 mg, crude) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 2.27-2.08 (m, 3H), 1.95 (d, 2H), 1.76 (d, 2H),
1.49-1.27 (m, 13H), 1.26-1.10 (m, 1H), 0.97-0.76 (m, 2H).
Intermediate 18
trans-4-(Benzyloxy)cyclohexanecarbonyl chloride
##STR00687##
[0672] Step 1: trans-Methyl 4-(benzyloxy)cyclohexanecarboxylate
[0673] Benzyl bromide (4.76 g, 27.81 mmol) was added in one portion
to a mixture of trans-methyl 4-hydroxycyclohexanecarboxylate (4.00
g, 25.28 mmol) and iPr.sub.2NEt (7.40 g, 57.26 mmol) under N.sub.2.
The mixture was stirred at 150.degree. C. for 8 h in sealed tube
and then allowed to cool to rt. Aqueous hydrochloric acid (1 N, 40
mL) was added to the resulting heterogeneous mixture. The mixture
was extracted with EtOAc (3.times.20 mL). The combined organics
were dried (MgSO.sub.4) and concentrated to give trans-methyl
4-(benzyloxy)cyclohexanecarboxylate (6.00 g, crude) as a yellow
oil.
Step 2: trans-4-(Benzyloxy)cyclohexanecarboxylic acid
[0674] Aqueous sodium hydroxide (5 M, 10 mL) was added in one
portion to a mixture of trans-methyl
4-(benzyloxy)cyclohexanecarboxylate (6.00 g, 24.16 mmol),
CH.sub.3OH (20 mL), and THF (20 mL) at rt under Na. The mixture was
stirred at rt overnight, neutralized to pH=1 with 5 N HCl and then
concentrated. The mixture was partitioned between EtOAc (30 mL) and
water (30 mL). The layers were separated. The aqueous layer was
extracted with EtOAc (2.times.15 mL). The combined organics were
concentrated to give trans-4-(benzyloxy)cyclohexanecarboxylic acid
(4.00 g, 71%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.32-7.36 (m, 4H), 7.23-7.29 (m, 1H), 4.56 (s, 2H)
3.26-3.41 (m, 1H), 2.27-2.37 (m, 1H), 2.13-2.18 (m, 2H), 2.04-2.08
(m, 2H), 1.42-1.55 (m, 2H), 1.26-1.40 (m, 2H); LCMS: 233.1
[M-H].sup.+.
Step 3: trans-4-(Benzyloxy)cyclohexanecarbonyl chloride
[0675] trans-4-(Benzyloxy)cyclohexanecarboxylic acid (600.3 mg,
2.56 mmol) was added in one portion to a mixture of
N-(chloromethylene)-N-methylmethanaminium chloride (655.6 mg, 5.12
mmol), K.sub.2CO.sub.3 (1.06 g, 7.68 mmol), and toluene (10.0 mL)
under N.sub.2. The mixture was stirred at rt for 1 h and then
filtered to give trans-4-(benzyloxy)cyclohexanecarbonyl chloride as
a clear solution. The solution was used immediately without
purification.
[0676] The Intermediate below was synthesized using 4-methoxybenzyl
bromide following the procedures described for Intermediate 18.
TABLE-US-00011 Int Structure Name 18.01 ##STR00688## trans-4-((4-
Methoxybenzyl)oxy)cyclohexanecarbonyl chloride
Intermediate 19
trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarbonyl
chloride
##STR00689##
[0677] Step 1: trans-tert-Butyldimethylsilyl
4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate
[0678] tert-Butyldimethylsilyl chloride (31.47 g, 208.8 mmol) was
added to a mixture of trans-4-hydroxy-cyclohexanecarboxylic acid
(10.03 g, 69.57 mmol), imidazole (18.96 g, 278.5 mmol), and DMF
(140 mL) at rt under N.sub.2 (reaction exothermed to 32.degree.
C.). The reaction was stirred at rt for 2 h and then diluted with
diethyl ether (300 mL). The organic layer was washed (2.times.300
mL 1 N HCl and then 300 mL brine), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give trans-tert-butyldimethylsilyl
4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g) as
a clear oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 3.61-3.53
(m, 1H), 2.26-2.18 (m, 1H), 2.04-1.96 (m, 2H), 1.92-1.85 (m, 2H),
1.51-1.39 (m, 2H), 1.39-1.27 (m, 2H), 0.94 (s, 9H), 0.89 (s, 9H),
0.26 (s, 6H), 0.06 (s, 6H).
Step 2: trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarboxylic
acid
[0679] Potassium carbonate (58.01 g, 419.7 mmol) in H.sub.2O (300
mL) was added to a mixture of trans-tert-butyldimethylsilyl
4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g
crude, 69.6 mmol), ethanol (1000 mL) and THF (300 mL) at rt under
N.sub.2. The reaction was stirred at rt for 3 h, concentrated until
300 mL remained, diluted with brine (600 mL), and then acidified to
pH 2-3 with 20% NaHSO4 (550 mL). The aqueous layer was extracted
with diethyl ether (800 mL). The organic layer was washed (800 mL
brine), dried (Na.sub.2SO.sub.4), filtered and concentrated to give
trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid
(17.3 g, 96% over 2 steps) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.30 (br s, 1H), 3.59-3.51 (m, 1H),
2.15-2.05 (m, 1H), 1.88-1.74 (m, 4H), 1.41-1.29 (m, 2H), 1.28-1.16
(m, 2H), 0.84 (s, 9H), 0.02 (s, 6H).
Step 3: trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarbonyl
chloride
[0680] (Chloromethylene)dimethyl iminium chloride (34.02 g, 265.78
mmol) was weighed into a 1000 mL round bottom flask (3 neck) and
degassed with vacuum/N.sub.2 cycles (3.times.). Toluene (240 mL)
was added to the flask, and the mixture was cooled (1.3.degree. C.)
in an ice bath. Anhydrous potassium carbonate* (68.71 g, 497.14
mmol) and
trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid
(34.29 g, 132.69 mmol) were sequentially added to the reaction. The
ice bath was removed, and the mixture was stirred for 35 min.
Celite (7 g) was added to the reaction, and then the reaction was
filtered through Celite (70 g, Chemglass 465 mL fritted funnel)
with toluene washes (3.times.100 mL). This solution (451 g, 8.5%
acid chloride, 100% yield, 72 mg/mL) was used immediately in the
acylation reaction. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
3.77-3.68 (m, 1H), 2.83-2.74 (m, 1H), 2.31-2.22 (m, 2H), 2.09-1.99
(m, 2H), 1.76-1.63 (m, 2H), 1.54-1.42 (m, 2H), 1.02 (s, 9H), 0.20
(s, 6H).
*Potassium carbonate was dried under vacuum by heating with a heat
gun for .about.5 min and then allowing to cool overnight.
[0681] The Intermediates below were synthesized from the
appropriate starting material or Intermediate following the
procedures described for Intermediate 19.
TABLE-US-00012 Int Structure Name 19.01 ##STR00690## cis-4-((tert-
Butyldimethylsilyl)oxy)cyclohexane- carbonyl chloride 19.02.sup.1
##STR00691## tert-Butyl (trans-4- (chlorocarbonyl)cyclohexyl)
carbamate 19.03.sup.1 ##STR00692## tert-Butyl ((trans-4-
(chlorocarbonyl)cyclohexyl)methyl) carbamate 19.04.sup.1
##STR00693## trans-methyl 4- (Chlorocarbonyl)cyclohexane-
carboxylate 19.05.sup.1 ##STR00694## Ethyl 2-(trans-4-
(chlorocarbonyl)cyclohexyl)acetate 19.06.sup.1 ##STR00695##
tert-Butyl 2-(trans-4- (chlorocarbonyl)cyclohexyl)acetate
19.07.sup.1 ##STR00696## tert-Butyl 3-(trans-4-
(chlorocarbonyl)cyclohexyl) propanoate 19.08.sup.1 ##STR00697##
trans-4-Cyanocyclohexanecarbonyl chloride 19.09.sup.1 ##STR00698##
trans-4- (Cyanomethyl)cyclohexanecarbonyl chloride 19.10.sup.2
##STR00699## 4-((tert-Butyldimethylsilyl)oxy)-4-
methylcyclohexanecarbonyl chloride .sup.1Step 3 only; .sup.2Step 1:
Ethyl 4-oxocyclohexanecarboxylate, AlMe.sub.3, toluene, 0
.degree.C., 1 h gave ethyl 4-
hydroxy-4-methylcyclohexanecarboxylate as a cis/trans mixture; Step
2: TBSOTf, 2,6-lutidine, DCM, 0 .degree.C.-rt, overnight; Step 3:
LiOH.cndot.H.sub.2O, H.sub.2O, THF; Step 4: Step 3 for Intermediate
19.
Intermediate 20
2-Hydroxyethyl (4-nitrophenyl) carbonate
##STR00700##
[0683] 4-Nitrophenyl carbonochloridate was added to a solution of
ethane-1,2-diol (230 mg, 3.70 mmol) and pyridine (293 mg, 3.70
mmol) in CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. under N.sub.2.
The mixture was allowed to warm to rt and stirred at rt for 3 h.
The reaction mixture was used in the next step without
purification.
Intermediate 21
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-iodophenyl)-N-((trans-4-(4-met-
hoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
##STR00701##
[0685] Intermediate 19 (74 mg/mL in toluene, 43 mL, 11.49 mmol) was
added to a solution of Intermediate 13 (3.32 g, 7.63 mmol),
pyridine (2.5 mL, 31 mmol), and toluene (15 mL). The mixture was
stirred at rt for 90 min, diluted with EtOAc (50 mL), and washed
(50 mL H.sub.2O, 50 mL sat'd NaHCO.sub.3 and then 50 mL brine). The
organic layer was dried (Na.sub.2SO.sub.4), filtered, concentrated,
and purified by silica gel chromatography (0-10% EtOAc in hexanes)
to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-iodophenyl)-N-((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (4.05
g, 79%) as a white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.76 (d, 1H), 7.72 (s, 1H), 7.31 (d, 1H), 7.27 (t, 1H),
6.97-6.92 (m, 2H), 6.80-6.76 (m, 1H), 3.72 (s, 3H), 3.60-3.40 (m,
3H), 2.37-2.27 (m, 1H), 2.09 (s, 3H), 2.01-1.91 (m, 1H), 1.78-1.67
(m, 6H), 1.65-1.56 (m, 2H), 1.49-1.21 (m, 5H), 1.10-0.94 (m, 2H),
0.92-0.76 (m, 11H), -0.01 (s, 6H); LCMS: 676.6 [M+H].sup.+.
[0686] The Intermediates below were synthesized from the
appropriate Intermediate following the procedure described for
Intermediate 21.
TABLE-US-00013 Int Structure Name [M + H].sup.+ 21.01 ##STR00702##
trans-4-((tert- Butyldimethylsilyl)oxy)-N- ((trans-4-(3-cyano-4-
methoxyphenyl)cyclohexyl) methyl)-N-(3- iodophenyl)
cyclohexanecarboxamide 687.5 21.02.sup.1 ##STR00703##
trans-N-(4-Bromopyridin- 2-yl)-4-((tert- butyldimethylsilyl)oxy)-
N-((trans-4-(4- methoxy-3- methylphenyl)cyclohexyl) methyl)
cyclohexanecarboxamide 629.2 21.03.sup.2 ##STR00704##
trans-4-((tert- Butyldimethylsilyl)oxy)-N-
(3-iodophenyl)-N-((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)cyclohexanecarboxamide 702.2
TABLE-US-00014 Int Structure Name [M + H].sup.+ 21.04.sup.1
##STR00705## trans-N-(4-Bromopyridin-2-yl)-4-((tert-
butyldimethylsilyl)oxy)-N-((4-(4-
methoxy-3-methylphenyl)bicyclo[2.2.2] octan-1-yl)methyl)
cyclohexanecarboxamide 655.2 21.05.sup.1 ##STR00706## trans-Methyl
4-((4-bromopyridin-2- yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylate
557.1 21.06.sup.1 ##STR00707## trans-Methyl
4-((4-bromopyridin-2-yl) ((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexane- carboxylate 583.1 21.07.sup.4
##STR00708## tert-butyl ((1R,4r)-4-((4-bromopyridin-
2-yl)(((1r,4R)-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)carbamate 614.0 21.08.sup.2 ##STR00709##
trans-Methyl 4-(((trans-4-(3-chloro-4-
methoxyphenyl)cyclohexyl)methyl)(3- (2-cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexane- carboxylate 621.6 21.09.sup.2
##STR00710## trans-Methyl 4-((3-(2-cyclopropyl-
thiazol-5-yl)phenyl)((trans-4-(3-fluoro- 1-methyl-1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 629.4
21.10.sup.2 ##STR00711## trans-Methyl 4-((3-(2-
cyclopropylthiazol-5-yl)phenyl)((4- (4-methoxy-3-methylphenyl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexane- carboxylate
627.5 21.11.sup.2 ##STR00712## trans-Methyl 4-((3-(2-cyclopropyl-
thiazol-5-yl)phenyl)((4-(6- (dimethylamino)pyridin-3-yl)
bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexanecarboxylate
672.8 21.12.sup.4 ##STR00713## trans-Methyl 4-((3-(2-cyclopropyl-
thiazol-5-yl)phenyl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 602.2
TABLE-US-00015 Int Structure Name [M + H].sup.+ 21.13.sup.3
##STR00714## trans-Methyl 4-((4-(2-cyclopropylthiazol-
5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 603.4
21.14.sup.2 ##STR00715## trans-Methyl 4-(((trans-4-(3-cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-(2- cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexanecarboxylate 612.4 21.15.sup.2
##STR00716## trans-Methyl 4-(((trans-4-(3-chloro-4-
methoxyphenyl)cyclohexyl)methyl)(3-(1- cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexanecarboxylate 604.7 21.16.sup.2
##STR00717## trans-Methyl 4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(3-fluoro-1- methyl-1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 612.4
21.17.sup.2 ##STR00718## trans-Methyl 4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecarboxylate 610.4 21.18.sup.4
##STR00719## trans-Methyl 4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl)
methyl)carbamoyl)cyclohexanecarboxylate 585.4 21.19.sup.2
##STR00720## trans-Methyl 4-(((trans-4-(3-cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-(1- cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexanecarboxylate 595.4 21.20.sup.5
##STR00721## trans-Methyl 4-((4-(1-isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 588.7
TABLE-US-00016 Int Structure Name [M + H].sup.+ 21.21.sup.2
##STR00722## trans-4-Cyano-N-(3-(2- cyclopropylthiazol-
5-yl)phenyl)-N-((trans-4- (4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 568.4
21.22.sup.2 ##STR00723## trans-4-(Cyanomethyl)-N-(3-(2-
cyclopropylthiazol-5-yl)phenyl)- N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 582.4
21.23.sup.2 ##STR00724## trans-4-Cyano-N-(3-(1- cyclopropyl-1H-
pyrazol-4-yl)phenyl)-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 551.4
Alternate conditions: .sup.1Et.sub.3N, CH.sub.2Cl.sub.2, rt,
overnight; .sup.2Solvent was CH.sub.2Cl.sub.2; .sup.3Amine in
pyridine only (no toluene); .sup.4DMAP, pyridine, 80 .degree.C.,
overnight; .sup.5DMAP, Et.sub.3N, toluene, 80 .degree.C., 90
min.
Intermediate 22
trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-
-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide
##STR00725##
[0687] Step 1:
N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)aniline
[0688] A mixture of Intermediate 13 (824 mg, 1.89 mmol),
bis(pinacolato)diboron (727 mg, 2.86 mmol), potassium acetate (373
mg, 3.80 mmol), Pd(dppf)Cl.sub.2 (141 mg, 0.19 mmol), and DMF (12
mL) was degassed with 3 vacuum/N.sub.2 cycles, heated at 80.degree.
C. for 24 h, and then allowed to cool to rt. The mixture was
filtered through Celite with EtOAc rinsing. The filtrate was washed
with 50 mL water, washed with 50 mL brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and purified by silica
gel chromatography (0-10% EtOAc in hexanes) to give
N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)aniline (563 mg, .about.90% pure,
.about.60% yield) as a green, sticky foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.07 (t, 1H), 7.01-6.95 (m, 2H), 6.95-6.91
(m, 1H), 6.84-6.79 (m, 2H), 6.70-6.65 (m, 1H), 5.63 (t, 1H), 3.73
(s, 3H), 2.90-2.85 (m, 2H), 2.43-2.33 (m, 1H), 2.11 (s, 3H),
1.96-1.88 (m, 2H), 1.82-1.75 (m, 2H), 1.63-1.52 (m, 1H), 1.44-1.33
(m, 2H), 1.27 (s, 12H), 1.13-1.03 (m, 2H); LCMS: 436.0
[M+H].sup.+.
Step 2:
N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(2-meth-
oxythiazol-5-yl)aniline
[0689] A mixture of
N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl) aniline (532 mg, 1.22 mmol),
5-bromo-2-methoxythiazole (363 mg, 1.87 mmol), Cs2CO.sub.3 (1.23 g,
3.77 mmol), Pd(PPh.sub.3).sub.4 (284 mg, 0.246 mmol), and DMF (6
mL) was degassed with 3 vacuum/N.sub.2 cycles. Water (60 .mu.L, 1%
by vol) was added, and the reaction was heated at 80.degree. C. for
4.5 h then allowed to cool to rt. The mixture was poured into 40 mL
sat'd NaHCO.sub.3 and extracted with EtOAc (2.times.40 mL). Each
extract was washed with 40 mL brine. The combined extracts were
dried (Na.sub.2SO.sub.4), filtered, concentrated, and purified by
silica gel chromatography (5-20% EtOAc in hexanes) to give
N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(2-methoxythia-
zol-5-yl)aniline (351 mg, 68%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.50-7.48 (m, 1H), 7.08 (t, 1H), 7.01-6.96
(m, 2H), 6.82-6.79 (m, 1H), 6.69-6.65 (m, 2H), 6.54-6.49 (m, 1H),
5.83 (t, 1H), 4.03 (s, 3H), 3.73 (s, 3H), 2.92 (t, 2H), 2.43-2.34
(m, 1H), 2.11 (s, 3H), 1.98-1.89 (m, 2H), 1.84-1.74 (m, 2H),
1.65-1.52 (m, 1H), 1.46-1.32 (m, 2H), 1.17-1.04 (m, 2H); LCMS:
423.4 [M+H].sup.+.
Step 3:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)
cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxam-
ide
[0690] A solution of Intermediate 19 (0.1 mL, 0.36 mmol) was added
to a solution of
N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(2-methoxythia-
zol-5-yl)aniline (148 mg, 0.35 mmol), pyridine (0.11 mL, 1.4 mmol),
and CH.sub.2Cl.sub.2 (3.5 mL) at rt. The reaction was stirred for
10 min, poured into 20 mL sat'd NaHCO.sub.3 and then extracted with
CH.sub.2Cl.sub.2. The organics were washed with 20 mL brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and purified by silica
gel chromatography (10-30% EtOAc in hexanes) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphe-
nyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarbo-
xamide (181 mg, .about.86% pure, 67% yield) as a white foam.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.75 (s, 1H),
7.56-7.46 (m, 3H), 7.26-7.20 (m, 1H), 6.98-6.92 (m, 2H), 6.81-6.76
(m, 1H), 4.06 (s, 3H), 3.72 (s, 3H), 3.60-3.44 (m, 3H), 2.38-2.28
(m, 1H), 2.09 (s, 3H), 2.07-1.99 (m, 1H), 1.79-1.68 (m, 6H),
1.68-1.60 (m, 2H), 1.50-1.37 (m, 3H), 1.36-1.23 (m, 2H), 1.12-0.98
(m, 2H), 0.91-0.76 (m, 11H), -0.02 (s, 6H); LCMS: 663.5
[M+H].sup.+.
Step 4:
trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)m-
ethyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide
[0691] Aqueous hydrochloric acid (6 N, 0.35 mL, 2.1 mmol) was added
to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphe-
nyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarbo-
xamide (176 mg, 0.265 mmol), CH.sub.3OH (1 mL) and THF (1 mL) at
rt. The reaction was stirred for 1 min, poured into 20 mL sat'd
NaHCO.sub.3, and then extracted with EtOAc (2.times.20 mL). The
combined extracts were washed with 20 mL sat'd NaHCO.sub.3, washed
with 20 mL brine, dried (Na.sub.2SO.sub.4), filtered, concentrated,
and purified by silica gel chromatography (40-90% EtOAc in hexanes)
to give
trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)--
N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide (68 mg,
93% pure, 50% yield) as an off-white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.76 (s, 1H), 7.57-7.47 (m, 3H), 7.27-7.21
(m, 1H), 6.98-6.92 (m, 2H), 6.81-6.75 (m, 1H), 4.41 (br s, 1H),
4.06 (s, 3H), 3.71 (s, 3H), 3.63-3.50 (m, 2H), 3.31-3.21 (m, 1H),
2.38-2.28 (m, 1H), 2.09 (s, 3H), 2.03-2.00 (m, 1H), 1.81-1.68 (m,
6H), 1.68-1.58 (m, 2H), 1.49-1.35 (m, 3H), 1.35-1.22 (m, 2H),
1.13-1.00 (m, 2H), 0.83-0.69 (m, 2H); LCMS: 549.4 [M+H].sup.+.
Intermediate 23
trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((tran-
s-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
##STR00726##
[0692] Step 1:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-y-
l)pyridin-2-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cy-
clohexanecarboxamide
[0693] A mixture of Intermediate 21.02 (800 mg, 1.27 mmol),
1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
(297.4 mg, 1.27 mmol), Cs2CO.sub.3 (827.8 mg, 2.54 mmol),
Pd(PPh.sub.3).sub.4 (146.8 mg, 0.127 mmol), DMF (10 mL) and
H.sub.2O (0.2 mL) was degassed with 3 vacuum/N.sub.2 cycles. The
mixture was stirred at 50.degree. C. under N.sub.2 for 1 h, allowed
to cool to rt, poured into water (50 mL), and then extracted with
EtOAc (3.times.50 mL).
[0694] The combined organic layers were washed with brine (50 mL),
dried over Na.sub.2SO.sub.4, filtered, concentrated and then
purified by chromatography on silica gel (petroleum
ether/EtOAc=80/20) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-y-
l)pyridin-2-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cy-
clohexanecarboxamide (720 mg, 86%) as a yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.46 (d, 1H), 7.86 (d, 2H), 7.29 (d,
1H), 7.22 (s, 1H), 6.97-6.92 (m, 2H), 6.73 (d, 1H), 3.79 (s, 3H),
3.76 (d, 2H), 3.72-3.65 (m, 1H), 3.60-3.50 (m, 1H), 2.41-2.31 (m,
1H), 2.27-2.16 (m, 4H), 1.90-1.79 (m, 8H), 1.67-1.57 (m, 3H),
1.41-1.30 (m, 2H), 1.23-1.05 (m, 8H), 0.84 (s, 9H), 0.02 (s, 6H);
LCMS: 657.5 [M+H].sup.+.
Step 2:
trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy--
N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxa-
mide
[0695] Aqueous hydrochloric acid (1 M, 1.7 mL, 1.7 mmol) was added
to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-y-
l)pyridin-2-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cy-
clohexanecarboxamide (720 mg, 1.10 mmol), CH.sub.3OH (10 mL) and
THF (10 mL) at 0.degree. C. The mixture was allowed to warm to rt
and stirred for 1 h. Saturated aq. NaHCO.sub.3 (40 mL) was added,
and the mixture was extracted with EtOAc (3.times.40 mL). The
combined organic layers were washed by brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
chromatography on silica gel (petroleum ether/EtOAc=60/40) to give
trans-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((tra-
ns-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(395.8 mg, 66%) as a white solid.
[0696] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.57 (s, 1H),
8.44 (d, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.57 (d, 1H), 6.97-6.89
(m, 2H), 6.80-6.72 (m, 1H), 4.41 (d, 1H), 3.81-3.73 (m, 1H), 3.71
(s, 3H), 3.67 (d, 2H), 3.31-3.21 (m, 1H), 2.33-2.26 (m, 1H),
2.19-2.10 (m, 1H), 2.08 (s, 3H), 1.81-1.67 (m, 8H), 1.47-1.35 (m,
3H), 1.30-1.20 (m, 2H), 1.12-1.06 (m, 2H), 1.06-0.94 (m, 4H),
0.88-0.74 (m, 2H); LCMS: 543.3 [M+H].sup.+.
[0697] The Intermediates below were synthesized from Intermediate
21.02 or Intermediate 21.04 and the appropriate boronic acid/ester
following the procedures described for Intermediate 23.
TABLE-US-00017 Int Structure Name [M + H].sup.+ 23.01 ##STR00727##
trans-N-(4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)-4-hydroxy-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 560.4 23.02
##STR00728## trans-N-(4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)-4-hydroxy-N-((4-(4- methoxy-3-methylphenyl)bicyclo
[2.2.2]octan-1-yl)methyl) cyclohexanecarboxamide 586.3 23.03
##STR00729## trans-N-(6-(Dimethylamino)-[3,4'-
bipyridin]-2'-yl)-4-hydroxy-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 557.5
[0698] The Intermediates below were synthesized from the
appropriate Intermediate and the appropriate boronic acid/ester
following the procedure described for Intermediate 23, Step 1.
TABLE-US-00018 Int Structure Name [M + H].sup.+ 23.04 ##STR00730##
trans-Methyl 4-((4-(2- cyclopropylthiazol-5-yl)pyridin-2-
yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexane- carboxylate 628.4 23.05
##STR00731## trans-Methyl 4-((4-(2-
cyclopropylthiazol-5-yl)pyridin-2- yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylate
602.2 23.06.sup.1 ##STR00732## trans-Methyl 4-((4-(1-cyclopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylate
585.2 23.07 ##STR00733## tert-Butyl (trans-4-((4-(1-cyclopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)carbamate
642.9 23.08 ##STR00734## tert-Butyl (trans-4-((4-(1-isopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)carbamate
644.6 Alternate conditions: .sup.1Pd(PPh.sub.3).sub.4,
K.sub.2CO.sub.3, dioxane, water (10%), 100 .degree.C., 2 h.
Intermediate 24
trans-N-(3-(6-(Dimethylamino)pyridine-3-yl)phenyl)-4-hydroxy-N-((trans-4-(-
4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
##STR00735##
[0699] Step 1:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(6-(dimethylamino)pyridine-3--
yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide
[0700] A mixture of Intermediate 21 (130 mg, 0.192 mmol),
(6-(dimethylamino)pyridine-3-yl)boronic acid (50 mg, 0.301 mmol),
K.sub.2CO.sub.3 (85 mg, 0.615 mmol), Pd(dppf)Cl.sub.2 (15 mg, 0.021
mmol), dioxane (1.8 mL), and H.sub.2O (1.3 mL) was degassed with
vacuum/nitrogen cycles (3.times.), heated at 80.degree. C. for 25
min, and then cooled to rt. The reaction was diluted with EtOAc (20
mL), washed (2.times.20 mL H.sub.2O), dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified by silica gel chromatography
(0-25% EtOAc in hexanes) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(6-(dimethylamino)pyridine-3--
yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide as a white foam (93 mg, 72%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.47 (d, 1H), 7.87 (dd, 1H), 7.64 (d, 1H),
7.54-7.48 (m, 2H), 7.19 (d, 1H), 6.96-6.92 (m, 2H), 6.79-6.76 (m,
1H), 6.74 (d, 1H), 3.71 (s, 3H), 3.61-3.54 (m, 2H), 3.53-3.43 (m,
1H), 3.07 (s, 6H), 2.39-2.28 (m, 1H), 2.11-2.00 (m, 4H), 1.81-1.60
(m, 8H), 1.51-1.38 (m, 3H), 1.35-1.21 (m, 2H), 1.12-0.99 (m, 2H),
0.90-0.73 (m, 11H), -0.03 (s, 6H); LCMS: 670.6 [M+H].sup.+.
Step 2:
trans-N-(3-(6-(Dimethylamino)pyridine-3-yl)phenyl)-4-hydroxy-N-((t-
rans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
[0701] Aqueous hydrochloric acid (1 N, 0.25 mL, 0.25 mmol) was
added to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(6-(dimethylamino)
pyridine-3-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)me-
thyl)cyclohexanecarboxamide (85 mg, 0.127 mmol), CH.sub.3OH (0.5
mL), and THF (0.5 mL) at 0.degree. C. The ice bath was removed, and
the mixture was stirred for 1 h. The reaction was diluted with
EtOAc (20 mL), washed (20 mL saturated NaHCO.sub.3 and then 20 mL
brine), dried (Na.sub.2SO.sub.4), and concentrated. The residue was
purified by silica gel chromatography (0-5% CH.sub.3OH in
CH.sub.2Cl.sub.2) to give
trans-N-(3-(6-(dimethylamino)pyridine-3-yl)phenyl)-4-hydroxy-N-((trans-4--
(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
as a white foam (61 mg, 86%). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.47 (d, 1H), 7.87 (dd, 1H), 7.64 (d, 1H), 7.54-7.48 (m,
2H), 7.19 (d, 1H), 6.96-6.92 (m, 2H), 6.79-6.76 (m, 1H), 6.74 (d,
1H), 4.39 (d, 1H), 3.71 (s, 3H), 3.63-3.51 (m, 2H), 3.31-3.20 (m,
1H), 3.07 (s, 6H), 2.39-2.28 (m, 1H), 2.15-2.00 (m, 4H), 1.84-1.69
(m, 6H), 1.68-1.56 (m, 2H), 1.51-1.36 (m, 3H), 1.35-1.22 (m, 2H),
1.13-0.98 (m, 2H), 0.85-0.69 (m, 2H); LCMS: 556.5 [M+H].sup.+.
[0702] The following Intermediates were synthesized from the
appropriate iodide Intermediate and the appropriate boronic
acid/ester following the procedure described for Intermediate
24.
TABLE-US-00019 Int Structure Name [M + H].sup.+ 24.01 ##STR00736##
trans-N-(3-(6-Cyclopropylpyridin-3-
yl)phenyl)-4-hydroxy-N-((trans-4- (4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 553.5 24.02
##STR00737## trans-N-(3-(2- (Dimethylamino)pyrimidin-5-
yl)phenyl)-4-hydroxy-N-((trans-4- (4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 557.3 24.03
##STR00738## trans-N-((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)- 4-hydroxy-N-(3-(1-isopropyl-1H-
pyrazol-4- yl)phenyl)cyclohexanecarboxamide 555.5 24.04
##STR00739## trans-N-((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)- N-(3-(1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)-4- hydroxycyclohexanecarboxamide 553.5
Intermediate 25
trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphen-
yl)cyclohexyl)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl)cyclohexanecarboxamide
##STR00740##
[0704] A mixture of bis(pinacolato)diboron (1.42 g, 5.59 mmol),
potassium acetate (1.45 g, 14.8 mmol), Pd(dppf)Cl.sub.2 (135 mg,
0.18 mmol), and toluene (23 mL) was degassed with 3 vacuum/N.sub.2
cycles. Intermediate 21 (2.50 g, 3.70 mmol) was added to the
mixture, and the reaction was degassed with 2 vacuum/N.sub.2
cycles, heated at 115.degree. C. for 3.5 h, and then allowed to
cool to rt. The mixture was diluted with 75 mL EtOAc. The organics
were washed with sat'd NaHCO.sub.3 (2.times.75 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated, and dried on high
vacuum overnight to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphe-
nyl)cyclohexyl)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)cyclohexanecarboxamide (2.99 g, 120% crude product) as a
brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.82-7.78
(m, 1H), 7.61-7.57 (m, 1H), 7.43 (t, 1H), 7.27-7.24 (m, 1H),
6.99-6.94 (m, 2H), 6.74 (d, 1H), 3.80 (s, 3H), 3.72-3.45 (m, 3H),
2.44-2.33 (m, 1H), 2.20 (s, 3H), 2.11-2.01 (m, 1H), 1.90-1.76 (m,
6H), 1.75-1.65 (m, 3H), 1.58-1.47 (m, 2H), 1.42-1.32 (m, 14H),
1.24-1.10 (m, 2H), 1.06-0.92 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H);
LCMS: 676.6 [M+H].sup.+. Note: Intermediate 25 was also synthesized
from bromo version of Intermediate 21.
Intermediate 26
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-hydroxy-N-((trans-4-(4-met-
hoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
##STR00741##
[0705] Step 1:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(2-cyclopropylthiazol-5-yl)ph-
enyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanec-
arboxamide
[0706] A mixture of 5-bromo-2-cyclopropylthiazole (93 mg, 0.45
mmol), Intermediate 25 (204 mg, 0.302 mmol), Pd(dppf)Cl.sub.2 (23
mg, 0.031 mmol), Cs2CO.sub.3 (290 mg, 0.89 mmol), DMF (3 mL), and
water (30 .mu.L, 1% by vol) was degassed with 3 vacuum/N.sub.2
cycles, stirred at 80.degree. C. for 25 min, and then allowed to
cool to rt. The reaction was poured into 20 mL sat'd NaHCO.sub.3
and then extracted with 20 mL EtOAc. The organic layer was washed
with 20 mL brine, dried (Na.sub.2SO.sub.4), filtered, concentrated,
and purified by silica gel chromatography (5-20% EtOAc in hexanes)
to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropylthiazol-5-yl)ph-
enyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanec-
arboxamide (179 mg, 88%) as a white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.09 (s, 1H), 7.63-7.55 (m, 2H), 7.52 (t,
1H), 7.29-7.22 (m, 1H), 6.98-6.91 (m, 2H), 6.82-6.75 (m, 1H), 3.71
(s, 3H), 3.62-3.44 (m, 3H), 2.47-2.38 (m, 1H), 1.38-2.28 (m, 1H),
2.09 (s, 3H), 2.07-1.99 (m, 1H), 1.79-1.68 (m, 6H), 1.68-1.60 (m,
2H), 1.51-1.37 (m, 3H), 1.36-1.23 (m, 2H), 1.18-1.11 (m, 2H),
1.11-0.96 (m, 4H), 0.91-0.72 (m, 11H), -0.03 (s, 6H); LCMS: 673.4
[M+H].sup.+.
Step 2:
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-hydroxy-N-((trans--
4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
[0707] Aqueous hydrochloric acid (6 N, 0.35 mL, 2.1 mmol) was added
to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropylthiazol-5-yl)ph-
enyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanec-
arboxamide (174 mg, 0.26 mmol), CH.sub.3OH (0.7 mL), and THF (0.7
mL) at 0.degree. C. The reaction was allowed to warm to rt, stirred
at rt for 30 min, and then poured into 20 mL of cold sat'd
NaHCO.sub.3. The mixture was extracted with 20 mL EtOAc. The
organic layer was washed with 20 mL sat'd NaHCO.sub.3 and washed
with 20 mL brine. The first aqueous wash was back extracted with 10
mL EtOAc. The combined EtOAc extracts were dried
(Na.sub.2SO.sub.4), filtered, concentrated, and purified by silica
gel chromatography (0-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give
trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-hydroxy-N-((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (131
mg, 90%) as a white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.10 (s, 1H), 7.63-7.55 (m, 2H), 7.53 (t, 1H), 7.30-7.23
(m, 1H), 6.98-6.91 (m, 2H), 6.82-6.75 (m, 1H), 4.40 (d, 1H), 3.71
(s, 3H), 3.62-3.50 (m, 2H), 3.31-3.20 (m, 1H), 2.48-2.39 (m, 1H),
2.38-2.27 (m, 1H), 2.09 (s, 3H), 2.06-1.96 (m, 1H), 1.80-1.68 (m,
6H), 1.68-1.58 (m, 2H), 1.49-1.35 (m, 3H), 1.35-1.22 (m, 2H),
1.18-1.11 (m, 2H), 1.11-0.97 (m, 4H), 0.83-0.69 (m, 2H); LCMS:
559.9 [M+H].sup.+.
Intermediate 27
trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-
-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide
##STR00742##
[0708] Step 1: 5-Bromo-2-((trimethylsilyl)ethynyl)thiazole
[0709] n-Butyllithium (2.5 M in hexanes, 4.50 mL) was added to a
solution of 2-((trimethylsilyl)ethynyl)thiazole (2.00 g, 11.03
mmol) in THF (50 mL) at -78.degree. C. The mixture was stirred for
1 h at -78.degree. C. Bromine (1.59 g, 9.93 mmol) was added to the
mixture. The mixture was stirred for 1 h at -78.degree. C., poured
into saturated aq. NH.sub.4Cl (100 mL), and then extracted with
EtOAc (2.times.100 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
silica gel chromatography (petroleum ether/EtOAc=600/1 to 300/1) to
obtain 5-bromo-2-((trimethylsilyl)ethynyl)thiazole (1.80 g, 62%
yield) as a red oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.77 (s, 1H), 0.36 (s, 9H); LCMS: 260.0 [M+H].sup.+.
Step 2:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethyny-
l)phenyl)cyclohexanecarboxamide
[0710] To a solution of Intermediate 25 (900 mg, 1.33 mmol),
5-bromo-2-((trimethylsilyl)ethynyl)thiazole (693 mg, 2.66 mmol),
dioxane (12 mL) and H.sub.2O (2 mL) was added Pd(dppf)Cl.sub.2 (195
mg, 0.266 mmol) and Na2CO.sub.3 (285.9 mg, 2.70 mmol). The mixture
was degassed with 3 vacuum/N.sub.2 cycles, stirred for 2 h at
80.degree. C., and then allowed to cool to rt. The reaction was
diluted with H.sub.2O (30 mL) and then extracted with EtOAc
(2.times.50 mL). The combined organics were dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
column chromatography on silica gel (eluted with petroleum
ether/EtOAc=30/1 to 10/1) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphe-
nyl)cyclohexyl)methyl)-N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethynyl)pheny-
l)cyclohexanecarboxamide (230 mg, 24% yield) as a yellow oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.86 (s, 1H), 7.58 (d,
1H), 7.44 (t, 1H), 7.41 (s, 1H), 7.21 (d, 1H), 6.97-6.95 (m, 2H),
6.73 (d, 1H), 3.78 (s, 3H), 3.60 (d, 2H), 3.55-3.51 (m, 1H),
2.43-2.34 (m, 1H), 2.18 (s, 3H), 2.08-2.03 (m, 1H), 1.88-1.78 (m,
6H), 1.67-1.58 (m, 4H), 1.44-1.37 (m, 3H), 1.21-1.17 (m, 2H),
1.07-1.03 (m, 2H), 0.83 (s, 9H), 0.38 (s, 9H), 0.00 (s, 6H); LCMS:
729.3 [M+H].sup.+.
Step 3:
trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)m-
ethyl)-N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecar-
boxamide
[0711] Aqueous hydrochloric acid (1 M, 1 mL) was added to a
solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphe-
nyl)cyclohexyl)methyl)-N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethynyl)pheny-
l)cyclohexanecarboxamide (230 mg, 0.315 mmol) in CH.sub.3OH (6 mL)
at 0.degree. C. The mixture was stirred for 1 h at rt and
concentrated under reduced pressure. The reaction was diluted with
saturated aq. NaHCO.sub.3 (10 mL) and then extracted with
CH.sub.2Cl.sub.2 (2.times.10 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and concentrated to give
trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)--
N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecarboxamid-
e (180 mg, crude) as a yellow oil. LCMS: 615.5 [M+H].sup.+.
Step 4:
trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)m-
ethyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide
[0712] Potassium fluoride (68.7 mg, 1.18 mmol) was added to a
solution of
trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)--
N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecarboxamid-
e (180 mg, 0.293 mmol) in CH.sub.3CN (10 mL). The mixture was
stirred overnight at 70.degree. C. The resulting mixture was
filtered through filter paper to remove excess potassium fluoride.
The filtrate was concentrated and then purified by reverse-phase
HPLC (water (10 mM NH.sub.4HCO.sub.3)-MeCN) to obtain
trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)--
N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide (82.4 mg,
51% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 7.98 (d, 1H), 7.95 (d, 1H), 7.68-7.64 (m, 2H), 7.57 (t,
1H), 7.44 (d, 1H), 6.92 (s, 2H), 6.76 (d, 1H), 4.40 (d, 1H), 3.69
(s, 3H), 3.53 (d, 2H), 3.27-3.25 (m, 1H), 2.33-2.28 (m, 1H), 2.07
(s, 3H), 1.96 (t, 1H), 1.71-1.59 (m, 8H), 1.42-1.26 (m, 5H),
1.03-1.00 (m, 2H), 0.77-0.74 (m, 2H); LCMS: 543.2 [M+H].sup.+.
Intermediate 28
trans-4-Hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)m-
ethyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide
##STR00743##
[0713] Step 1:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bi-
cyclo[2.2.2]octan-1-yl)methyl)-N-(3-((trimethylsilyl)ethynyl)phenyl)cycloh-
exanecarboxamide
[0714] A mixture of Intermediate 21.03 (2.75 g, 3.92 mmol),
ethynyl(trimethyl)silane (384.9 mg, 3.92 mmol), CuI (74.6 mg, 0.392
mmol), Pd(dppf)Cl.sub.2 (286.7 mg, 0.392 mmol) and dry Et.sub.3N
(30 mL) was degassed with 3 vacuum/N.sub.2 cycles, stirred at
90.degree. C. under Na for 2 h, and then allowed to cool to rt. The
reaction was poured into 100 mL water and extracted with EtOAc
(2.times.100 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
chromatography on silica gel (petroleum ether/EtOAc=95/5) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bi-
cyclo[2.2.2]octan-1-yl)methyl)-N-(3-((trimethylsilyl)ethynyl)phenyl)cycloh-
exanecarboxamide (2.12 g, 81%) as a white solid. .sup.1H NMR (400
MHz,CDCl.sub.3): .delta. 7.43-7.39 (m, 1H), 7.35-7.30 (m, 2H), 7.20
(d, 1H), 7.07-7.02 (m, 2H), 6.73 (d, 1H), 3.79 (s, 3H), 3.73-3.39
(m, 3H), 2.23-2.17 (m, 4H), 1.84-1.79 (m, 2H), 1.76-1.63 (m, 10H),
1.50-1.43 (m, 6H), 1.09-0.99 (m, 2H), 0.93-0.82 (m, 9H), 0.29 (s,
9H), 0.02 (s, 6H); LCMS: 672.3 [M+H].sup.+.
Step 2:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-ethynylphenyl)-N-((4-(-
4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarbox-
amide
[0715] Ammonium fluoride (688.8 mg, 18.60 mmol) was added to a
solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bi-
cyclo[2.2.2]octan-1-yl)methyl)-N-(3-((trimethylsilyl)ethynyl)phenyl)cycloh-
exanecarboxamide (2.5 g, 3.72 mmol) in CH.sub.3OH (50 mL) at rt.
The reaction was warmed to 60.degree. C., stirred for 3 h, and then
allowed to cool to rt. The reaction mixture was concentrated to
dryness and purified by chromatography on silica gel (petroleum
ether/EtOAc=95/5) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-ethynylphenyl)-N-((4-(4--
methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxam-
ide (1.6 g, 72%) as a yellow solid. .sup.1H NMR (400
MHz,CDCl.sub.3): .delta. 7.47-7.42 (m, 1H), 7.40-7.34 (m, 2H), 7.24
(d, 1H), 7.08-7.02 (m, 2H), 6.74 (d, 1H), 3.79 (s, 3H), 3.62 (s,
2H), 3.57-3.50 (m, 1H), 3.16 (s, 1H), 2.24-2.12 (m, 4H), 1.86-1.78
(m, 2H), 1.77-1.57 (m, 10H), 1.50-1.43 (m, 6H), 1.10-0.97 (m, 2H),
0.85 (s, 9H), 0.02 (s, 6H); LCMS: 600.5 [M+H].sup.+.
Step 3:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylph-
enyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyc-
lohexanecarboxamide
[0716] A mixture of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-ethynylphenyl)-N-((4-(4-metho-
xy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide
(1.4 g, 2.33 mmol), 2-bromothiazole (765.6 mg, 4.67 mmol), CuI
(44.4 mg, 0.233 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (163.8 mg, 0.233
mmol) and dry Et.sub.3N (15 mL) was degassed with 3 vacuum/N.sub.2
cycles, stirred at 90.degree. C. under N.sub.2 for 1 h, and then
allowed to cool to rt. The reaction was poured into 90 mL water and
then extracted with EtOAc (3.times.100 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, concentrated,
and then purified by chromatography on silica gel (petroleum
ether/EtOAc=95/5) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bi-
cyclo[2.2.2]octan-1-yl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexan-
ecarboxamide (1.36 g) as a yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.91 (d, 1H), 7.49 (d, 1H), 7.46 (d, 1H),
7.43-7.39 (m, 2H), 7.29 (s, 1H), 7.07-7.03 (m, 2H), 6.76-6.72 (m,
1H), 3.79 (s, 3H), 3.62 (s, 2H), 3.57-3.50 (m, 1H), 2.21-2.13 (m,
4H), 1.87-1.79 (m, 2H), 1.77-1.56 (m, 10H), 1.50-1.43 (m, 6H),
1.10-0.97 (m, 2H), 0.85 (s, 9H), 0.02 (s, 6H).
Step 4:
trans-4-Hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octa-
n-1-yl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide
[0717] Aqueous hydrochloric acid (1 M, 3 mL, 3.0 mmol) was added to
a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bi-
cyclo[2.2.2]octan-1-yl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexan-
ecarboxamide (1.36 g) in CH.sub.3OH (10 mL) and THF (10 mL) at
0.degree. C. The reaction was allowed to warm to rt and stirred for
1 h. Saturated aq. NaHCO.sub.3 (40 mL) was added, and the mixture
was extracted with EtOAc (3.times.40 mL). The combined organic
layers were washed by brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered, concentrated, and then purified by chromatography on
silica gel (CH.sub.2Cl.sub.2/CH.sub.3OH=97/3). The impure material
was further purified by reverse-phase prep-HPLC (water(10 mmol
NH.sub.4HCO.sub.3)/MeCN) to give
trans-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)-
methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide
(47.3 mg, 13%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.98 (d, 2H), 7.73 (s, 1H), 7.62 (s, 1H),
7.58-7.50 (m, 2H), 7.05-6.97 (m, 2H), 6.76 (d, 1H), 4.45-4.41 (m,
1H), 3.70 (s, 3H), 3.65-3.45 (m, 2H), 3.30-3.21 (m, 1H), 2.15-2.05
(m, 4H), 1.75 (d, 2H), 1.70-1.55 (m, 8H), 1.45-1.32 (m, 8H),
0.90-0.70 (m, 2H); LCMS: 569.3 [M+H].sup.+.
Intermediate 29
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(3-fluoro-1--
methyl-1H-indazol-5-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide
##STR00744##
[0718] Step 1:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(1-cyclopropyl-1H-pyrazol-4-y-
l)phenyl)-N-((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl-
)cyclohexanecarboxamide
[0719] Intermediate 19 (75 mg/mL toluene solution, 1.7 mL, 0.461
mmol) was added to a solution of Intermediate 14.25 (130 mg, 0.293
mmol), pyridine (95 .mu.L, 1.17 mmol), and toluene (2.5 mL) in an
rt H.sub.2O bath. The mixture was stirred at rt for 2 h, diluted
with EtOAc (20 mL), washed (20 mL saturated NaHCO.sub.3 and then 20
mL brine), dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The residue was purified by silica gel chromatography (0-40% EtOAc
in hexanes) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(1-cyclopropyl-1H-pyrazol-4-y-
l)phenyl)-N-((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl-
)cyclohexanecarboxamide (184 mg, 90%) as a white foam. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.93 (s, 1H), 7.60
(d, 1H), 7.54 (s, 1H), 7.50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (d,
1H), 7.10 (d, 1H), 3.86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.42 (m,
3H), 2.61-2.52 (m, 1H), 2.13-2.02 (m, 1H), 1.84-1.75 (m, 4H),
1.75-1.68 (m, 2H), 1.68-1.59 (m, 2H), 1.54-1.33 (m, 5H), 1.14-1.03
(m, 4H), 1.02-0.92 (m, 2H), 0.90-0.72 (m, 11H), -0.03 (s, 6H);
LCMS: 684.2 [M+H].sup.+.
Step 2:
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(3-f-
luoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarb-
oxamide
[0720] Aqueous hydrochloric acid (1 N, 0.5 mL, 0.5 mmol) was added
to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(1-cyclopropyl-1H-pyrazol-4-y-
l)phenyl)-N-((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl-
)cyclohexanecarboxamide (180 mg, 0.263 mmol), THF (1 mL), and
CH.sub.3OH (1 mL) at 0.degree. C. The ice bath was removed after 10
min, and the reaction was stirred for 50 min. The mixture was
diluted with EtOAc (20 mL), washed (2.times.20 mL saturated
NaHCO.sub.3 and then 20 mL brine), dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified by silica gel
chromatography (0-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(3-fluoro-1-
-methyl-1H-indazol-5-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide
(150 mg, 100%, 95% pure) as a white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H),
7.54 (s, 1H), 7.50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (dd, 1H), 7.10
(d, 1H), 4.38 (d, 1H), 3.86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.43
(m, 2H), 3.31-3.20 (m, 1H), 2.61-2.52 (m, 1H), 2.16-2.00 (m, 1H),
1.84-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.52-1.33 (m, 5H), 1.15-1.04
(m, 4H), 1.02-0.96 (m, 2H), 0.81-0.67 (m, 2H); LCMS: 570.4
[M+H].sup.+.
[0721] The Intermediates below were synthesized from the
appropriate secondary amine Intermediate and Intermediate 19
following the procedures described for Intermediate 29.
TABLE-US-00020 Int Structure Name [M + H].sup.+ 29.01 ##STR00745##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol- 4-yl)phenyl)-N-((trans-4-(6-
(dimethylamino)pyridin-3- yl)cyclohexyl)methyl)-4-
hydroxycyclohexanecarboxamide 542.4 29.02 ##STR00746##
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)-4-hydroxy-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexane- carboxamide 543.5 29.03.sup.1
##STR00747## trans-N-((trans-4-(6-Cyano-5-methoxypyridin-2-
yl)cyclohexyl)methyl)-N-(3-(1- cyclopropyl-1H-pyrazol-4-yl)phenyl)-
4-hydroxycyclohexanecarboxamide 554.5 29.04.sup.1 ##STR00748##
trans-4-Hydroxy-N-(3-(1-isopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl) cyclohexanecarboxamide 545.5
29.05.sup.1 ##STR00749##
trans-N-((trans-4-(5-chloro-6-methoxypyridin-3-
yl)cyclohexyl)methyl)-N-(3-(1- cyclopropyl-1H-pyrazol-4-yl)
phenyl)-4-hydroxycyclohexane- carboxamide 563.5 29.06.sup.1
##STR00750## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-hydroxy-N-((trans-4-(6- methoxy-5-methylpyridin-3-
yl)cyclohexyl)methyl)cyclohexane- carboxamide 543.4 29.07.sup.1
##STR00751## trans-N-(3-(1-(tert-Butyl)-1H-pyrazol-4-
yl)phenyl)-4-hydroxy-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 559.5 29.08.sup.1
##STR00752## trans-N-(3-(1-Cyclobutyl-1H-pyrazol-4-
yl)phenyl)-4-hydroxy-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 557.5 29.09.sup.1,2
##STR00753## trans-4-Hydroxy-N-(4-(1-isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-
(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 546.5 29.10.sup.1
##STR00754## trans-N-((trans-4-(6-Cyano-5-methoxypyridin-2-
yl)cyclohexyl)methyl)-4-hyroxy-N-(3- (1-isopropyl-1H-pyrazol-4-
yl)phenyl)cyclohexanecarboxamide 556.5 29.11 ##STR00755##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-hydroxy-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 542.5 29.12
##STR00756## trans-4-Hydroxy-N-(3-(1-isopropyl-1H-
pyrazol-4-yl)phenyl)-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 544.4
29.13.sup.1 ##STR00757## trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-
3-methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)cyclohexanecarboxamide 568.4 29.14 ##STR00758##
trans-N-(3-(2-cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(3-fluoro-1- methyl-1H-indazol-5-
yl)cyclohexyl)methyl)-4- hydroxycyclohexanecarboxamide 587.9 29.15
##STR00759## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(6- (dimethylamino)pyridin-3-
yl)cyclohexyl)methyl)-4- hydroxycyclohexanecarboxamide 559.4
29.16.sup.1 ##STR00760## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-
3-methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)cyclohexanecarboxamide 585.4 29.17.sup.1,2 ##STR00761##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-hydroxy-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 560.3 29.18.sup.1,2
##STR00762## trans-N-(4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-
(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 561.4 29.19.sup.1
##STR00763## trans-N-((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)-N-(3-(2- cyclopropylthiazol-5-yl)phenyl)-4-
hydroxycyclohexanecarboxamide 571.3 29.20.sup.1 ##STR00764##
trans-4-Hydroxy-N-(3-(2- isopropylthiazol-5-yl)phenyl)-N-((trans-
4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 562.4 29.21.sup.1,3
##STR00765## (1r,4r)-4-Hydroxy-N-(3-(1-isopropyl-1H-
pyrazol-4-yl)phenyl)-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- methylcyclohexanecarboxamide
558.3 29.22.sup.4 ##STR00766## (1s,4s)-4-Hydroxy-N-(3-(1-isopropyl-
1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- methylcyclohexanecarboxamide
558.3 Alternate conditions: Step 1: .sup.1Solvent was
CH.sub.2Cl.sub.2; .sup.2Base was Et.sub.3N; Step 2: .sup.33M HCl,
THF, MeOH, 45 .degree.C., overnight. .sup.4Isolated during the
purification of Intermediate 29.21.
Intermediate 30 (M1125, 050-102/106)
trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((tran-
s-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxami-
de
##STR00767##
[0722] Step 1:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-y-
l)pyridin-2-yl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)met-
hyl)cyclohexanecarboxamide
[0723] Intermediate 19 (1.6 mL, 0.42 mmol, 73 mg/mL in toluene) was
added to a mixture of Intermediate 14.29 (87 mg, 0.21 mmol), DMAP
(26 mg, 0.21 mmol) and pyridine (1.5 mL) at rt. The reaction was
heated at 80.degree. C. for 75 min, allowed to cool to rt and then
diluted with EtOAc (20 mL). The organic layer was washed with
saturated NaHCO.sub.3 (20 mL), washed with water (20 mL), washed
with brine (20 mL), dried (Na.sub.2SO.sub.4), filtered,
concentrated, and then purified by silica gel chromatography
(30-60% EtOAc in hexanes) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-y-
l)pyridin-2-yl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)met-
hyl)cyclohexanecarboxamide (114 mg, 82% yield) as an off-white
foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.57 (s, 1H),
8.43 (d, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.57 (d, 1H), 7.18 (d,
1H), 6.97 (d, 1H), 3.81-3.72 (m, 4H), 3.67 (d, 2H), 3.57-3.47 (m,
1H), 2.51-2.42 (m, 1H), 2.28 (s, 3H), 2.25-2.11 (m, 1H), 1.84-1.69
(m, 8H), 1.50-1.26 (m, 5H), 1.12-0.84 (m, 8H), 0.80 (s, 9H), -0.02
(s, 6H); LCMS: 658.6 [M+H].sup.+.
Step 2:
trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy--
N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanec-
arboxamide
[0724] A solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-y-
l)pyridin-2-yl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)met-
hyl)cyclohexanecarboxamide (107 mg, 0.16 mmol) in THF (1 mL) and
CH.sub.3OH (1 mL) was cooled in an ice/water bath. Aqueous
hydrochloric acid (1 N, 0.22 mL, 0.22 mmol) was added at 0.degree.
C. The reaction was allowed to warm to rt, stirred for 20 min and
then diluted with chilled saturated NaHCO.sub.3 (20 mL) and EtOAc
(20 mL). The organic layer was washed with saturated NaHCO.sub.3
(20 mL), washed with brine (20 mL), dried (Na.sub.2SO.sub.4),
filtered, concentrated, and then purified by silica gel
chromatography (0-7% methanol in dichloromethane) to give
trans-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((tra-
ns-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxam-
ide (79 mg, 89% yield) as a white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.57 (s, 1H), 8.44 (d, 1H), 8.13 (s, 1H),
7.64 (s, 1H), 7.57 (dd, 1H), 7.19 (d, 1H), 6.98 (d, 1H), 4.41 (d,
1H), 3.81-3.72 (m, 4H), 3.67 (d, 2H), 3.31-3.22 (m, 1H), 2.51-2.42
(m, 1H), 2.28 (s, 3H), 2.19-2.09 (m, 1H), 1.83-1.67 (m, 8H),
1.48-1.26 (m, 5H), 1.12-0.94 (m, 6H), 0.88-0.75 (m, 2H); LCMS:
544.5 [M+H].sup.+.
[0725] The Intermediates below were synthesized from the
appropriate secondary amine Intermediate and Intermediate 19
following the procedures described for Intermediate 30.
TABLE-US-00021 Int Structure Name [M + H].sup.+ 30.01 ##STR00768##
trans-N-(4-(1-Cyclopropyl- 1H-pyrazol- 4-yl)-6-methylpyridin-
2-yl)-4-hydroxy- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 557.7 30.02
##STR00769## trans-4-Hydroxy-N-(4- (1-isopropyl-1H-
pyrazol-4-yl)pyridin- 2-yl)-N-((trans-4- (4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 545.5
30.03.sup.1 ##STR00770## trans-N-((trans-4-(3-Cyano-4-
methoxyphenyl) cyclohexyl)methyl)-N-
(4-(1-cyclopropyl-1H-pyrazol-4- yl)pyridin-2-yl)-4-
hydroxycyclohexanecarboxamide 554.4 30.04.sup.1 ##STR00771##
trans-N-((trans-4-(3-Cyano-4- methoxyphenyl) cyclohexyl)methyl)-4-
hydroxy-N-(4-(1- isopropyl-1H-pyrazol- 4-yl)pyridin-2-
yl)cyclohexanecarboxamide 556.4 30.05.sup.1 ##STR00772##
cis-N-((4-(3-Cyano-4- methoxyphenyl)cyclohexyl) methyl)-4-
hydroxy-N-(4-(1- isopropyl-1H-pyrazol- 4-yl)pyridin-2-
yl)cyclohexanecarboxamide 556.4 30.06.sup.1 ##STR00773##
trans-N-((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)- 4-hydroxy-N-(4- (1-isopropyl-1H-pyrazol-
4-yl)pyridin-2- yl)cyclohexanecarboxamide 557.4 30.07.sup.1,2
##STR00774## trans-N-(3-(1-Cyclopropyl- 1H-pyrazol-
4-yl)phenyl)-N-((4-(6- (dimethylamino)pyridin-3-
yl)bicyclo[2.2.2]octan- 1-yl)methyl)-4-
hydroxycyclohexanecarboxamide 568.5 30.08.sup.1 ##STR00775##
trans-N-((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)-N-(4-(1- cyclopropyl-1H-pyrazol-
4-yl)pyridin-2- yl)-4- hydroxycyclohexanecarboxamide 555.5 30.09
##STR00776## trans-N-((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl) methyl)-N-(4-(2-
cyclopropylthiazol-5-yl)pyridin-2- yl)-4-
hydroxycyclohexanecarboxamide 571.4 30.10.sup.1 ##STR00777##
trans-N-((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)-N-(4-(2- cyclopropylthiazol-5-yl)
pyridin-2-yl)-4-hydroxycyclo- hexanecarboxamide 572.4 30.11
##STR00778## trans-4-Hydroxy-N-(4-(2- isopropylthiazol-5-yl)
pyridin-2-yl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 562.5
30.12.sup.1 ##STR00779## trans-4-Hydroxy-N-(4-(2-
isopropylthiazol-5-yl)pyridin-2-yl)- N-((trans-4-(5-methoxy-6-
methylpyridin-2- yl)cyclohexyl)methyl) cyclohexanecarboxamide 563.4
30.13 ##STR00780## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((4-(6- (dimethylamino)pyridin-3-
yl)bicyclo[2.2.2]octan- 1-yl)methyl)-4-
hydroxycyclohexanecarboxamide 585.5 30.14.sup.2 ##STR00781##
trans-N-(3-(2-Cyclopropyloxazol-4- yl)phenyl)-N-((4-(6-
(dimethylamino)pyridine-3- yl)pyridin[2.2.2]octan-1-yl) methyl)-4-
hydroxycyclohexanecarboxamide 569.5 30.15.sup.1 ##STR00782##
trans-N-((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)-
N-(4-(2-cyclopropyloxazol-4-yl) pyridine-2-yl)-4-
hydroxycyclohexanecarboxamide 555.5 30.16 ##STR00783##
trans-N-((trans-4-(3-Cyano-4- methoxyphenyl)cyclohexyl)
methyl)-N-(4-(2-cyclopropyl- oxazol-4-yl)pyridine-2- yl)-4-
hydroxycyclohexanecarboxamide 557.4 30.17 ##STR00784##
trans-N-((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)-N-(4-(2- cyclopropylthiazol-4-yl)
pyridine-2-yl)-4- hydroxycyclohexanecarboxamide 556.4 30.18.sup.3
##STR00785## trans-N-(4-(2-Ethyloxazol-
4-yl)pyridin-2-yl)-4-hydroxy-N- ((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl) methyl) cyclohexanecarboxamide 533.4
Alternate conditions: Step 1: .sup.1Additional acid chloride
needed, 2.5-3.5 eq total; .sup.2Heated at 50 .degree.C.;
.sup.3DMAP, Et.sub.3N, toluene, 80 .degree.C., 20 min.
Intermediate 31
trans-N-(3-(3-Cyclopropylisothiazol-5-yl)phenyl)-4-hydroxy-N-((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
##STR00786##
[0726] Step 1:
3-(3-Cyclopropylisothiazol-5-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cy-
clohexyl)methyl)aniline
[0727] A mixture of Intermediate 9 (140 mg, 0.647 mmol),
Intermediate 3 (165 mg, 0.712 mmol), AcOH (117 mg, 1.94 mmol), and
CH.sub.3OH (10 mL) was degassed with vacuum/N.sub.2 cycles
(3.times.) and stirred at rt for 2 h. NaBH.sub.3CN (81 mg, 1.29
mmol) was added to the mixture, and the reaction was stirred at rt
overnight. The solution was concentrated and purified by silica gel
chromatography (petroleum ether/EtOAc=5/1) to give
3-(3-cyclopropylisothiazol-5-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cy-
clohexyl)methyl)aniline (200 mg, 71%) as a yellow solid. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.22 (t, 1H), 7.07 (s, 1H),
7.00-7.05(m, 2H), 6.86-6.93 (m, 1H), 6.77 (d, 2H), 6.65-6.67 (m,
1H), 3.86-3.93 (m, 1H), 3.82 (s, 3H), 3.06 (d, 2H), 2.35-2.52 (m,
1H), 2.22 (s, 3H), 2.13-2.20 (m, 1H), 1.89-2.03 (m, 4H), 1.61-1.75
(m, 1H), 1.43-1.53 (m, 2H), 1.17-1.25 (m, 2H), 0.98-1.08 (m, 4H);
LCMS: 433.2 [M+H].sup.+.
Step 2:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(3-cyclopropylisothiaz-
ol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cy-
clohexanecarboxamide
[0728] Pyridine (110 mg, 1.39 mmol) was added to a solution of
3-(3-cyclopropylisothiazol-5-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cy-
clohexyl)methyl)aniline (200 mg, 0.462 mmol) and CH.sub.2Cl.sub.2
(10.0 mL) at rt. The solution was stirred at rt for 30 min, and
Intermediate 19 (384 mg, 1.39 mmol) was added. The mixture was
stirred overnight, concentrated, and purified by silica gel
chromatography (petroleum ether/EtOAc=5/1) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(3-cyclopropylisothiazol-5-yl-
)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexa-
necarboxamide (250 mg, 80%) as a colorless oil. LCMS: 673.5
[M+H].sup.+.
Step 3:
trans-N-(3-(3-Cyclopropylisothiazol-5-yl)phenyl)-4-hydroxy-N-((tra-
ns-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
[0729] Aqueous hydrochloric acid (2 M, 450 uL, 0.9 mmol) was slowly
added to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(3-cyclopropylisothiazol-5-yl-
)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexa-
necarboxamide (250 mg, 0.371 mmol) and CH.sub.3OH (10 mL). The
solution was stirred at rt for 1 h, concentrated, and then purified
by RP-HPLC (H.sub.2O(10 mM NH.sub.4HCO.sub.3)/CH.sub.3CN) to give
trans-N-(3-(3-cyclopropylisothiazol-5-yl)phenyl)-4-hydroxy-N-((trans-4-(4-
-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(112 mg, 54%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.67-7.71 (m, 2H), 7.65 (s, 1H), 7.58 (t,
1H), 7.38 (d, 1H), 6.91-6.97 (m, 2H), 6.75-6.81 (m, 1H), 3.71 (s,
3H), 3.53-3.64 (m, 2H), 3.20-3.29 (m, 1H), 2.33 (t, 1H), 2.17-2.25
(m, 1H), 2.09 (s, 3H), 2.01-2.07 (m, 1H), 1.62-1.81 (m, 8H),
1.23-1.48 (m, 5H), 0.92-1.11 (m, 6H), 0.69-0.84 (m, 2H); LCMS:
559.6 [M+H].sup.+.
Intermediate 32
trans-N-(3-(2-Cyclopropyloxazol-4-yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-3--
methylphenyl)pyridin[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide
##STR00787##
[0730] Step 1:
3-(2-Cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)
pyridin[2.2.2]octan-1-yl)methyl)aniline
[0731] Sodium triacetoxyborohydride (496 mg, 2.34 mmol) was added
to a solution of Intermediate 5 (302 mg, 1.17 mmol), Intermediate
8.01 (236 mg, 1.18 mmol), and DCE (6 mL) at 0.degree. C. The ice
bath was removed, and the reaction was stirred at rt for 1 h. The
mixture was diluted with EtOAc (50 mL), washed (2.times.50 mL
saturated NaHCO.sub.3 and then 50 mL brine), dried
(Na.sub.2SO.sub.4), filtered, and then concentrated. The residue
was purified by silica gel chromatography (petroleum
ether/EtOAc=20:1 to 5:1) to give
3-(2-cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)pyridin[2.2.-
2]octan-1-yl)methyl)aniline (471 mg, 90%) as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.71 (s, 1H), 7.14-7.21
(m, 1H), 7.08-7.14 (m, 2H), 7.02 (s, 1H), 6.96 (d, 1H), 6.77 (d,
1H), 6.52-6.59 (m, 1H), 3.81 (s, 3H), 3.72 (br s, 1H), 2.95-2.96
(m, 2H), 2.22 (s, 3H), 2.11-2.16 (m, 1H), 1.80-1.91 (m, 6H),
1.58-1.68 (m, 6H), 1.00-1.20 (m, 4H); LCMS: 443.3 [M+H].sup.+.
Step 2:
trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(2-cyclopropyloxazol-4-
-yl)phenyl)-N-((4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methy-
l)cyclohexanecarboxamide
[0732] Intermediate 19 (20 mL, 2.79 mmol, 4.3 wt % toluene
solution,) was added to a solution of
3-(2-cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)pyridin[2.2.-
2]octan-1-yl)methyl)aniline (471 mg, 1.06 mmol), pyridine (337 mg,
4.26 mmol), and toluene (8 mL) at 0.degree. C. The ice bath was
removed, and the reaction was stirred at rt for 1 h. The mixture
was diluted with H.sub.2O (50 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic extracts were washed (100 mL
brine), dried (Na.sub.2SO.sub.4), filtered, and then concentrated.
The residue was purified by silica gel chromatography (petroleum
ether/EtOAc=20/1 to 5/1) to give
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropyloxazol-4-yl)phe-
nyl)-N-((4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methyl)cyclo-
hexanecarboxamide (533 mg, 74%) as a colorless oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.50 (s, 1H), 7.63-7.69 (m, 2H),
7.45 (t, 1H), 7.28 (d, 1H), 6.95-7.02 (m, 2H), 6.74 (d, 1H), 3.68
(s, 3H), 3.42-3.61 (m, 3H), 2.10-2.18 (m, 2H) 2.06 (s, 3H),
1.67-1.85 (m, 4H), 1.55-1.63 (m, 7H), 1.29-1.46 (m, 9H), 0.93-1.10
(m, 4H), 0.76 (s, 9H), -0.05 (s, 6H); LCMS: 683.5 [M+H].sup.+.
Step 3:
trans-N-(3-(2-Cyclopropyloxazol-4-yl)phenyl)-4-hydroxy-N-((4-(4-me-
thoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamid-
e
[0733] Aqueous hydrochloric acid (1 N, 1.2 mL, 1.2 mmol) was slowly
added to a solution of
trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropyloxazol-4-yl)phe-
nyl)-N-((4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methyl)cyclo-
hexanecarboxamide (533 mg, 0.780 mmol), THF (4 mL), and CH.sub.3OH
(4 mL) at 0.degree. C. The ice bath was removed, and the reaction
was stirred at rt for 1 h. The mixture was diluted with H.sub.2O
(50 mL) and extracted with EtOAc (3.times.50 mL). The combined
organic extracts were washed (100 mL brine), dried
(Na.sub.2SO.sub.4), filtered, and then concentrated. The residue
was purified by silica gel chromatography (petroleum
ether/EtOAc=10/1 to 2/1 and then CH.sub.2Cl.sub.2/CH.sub.3OH=10/1)
to give
trans-N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-3-
-methylphenyl)pyridin[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide
(364 mg, 82%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.53 (s, 1H), 7.73-7.76 (m, 2H), 7.48 (t,
1H), 7.31 (d, 1H), 6.95-7.07 (m, 2H), 6.77 (d, 1H), 4.41 (d, 1H),
3.52-3.70 (m, 5H), 3.19-3.30 (m, 1H), 2.11-2.22 (m, 2H), 2.08 (s,
3H), 1.71-1.75 (m, 2H), 1.54-1.67 (m, 8H), 1.32-1.47 (m, 8H),
0.96-1.11 (m, 4H), 0.68-0.82 (m, 2H); LCMS: 569.3 [M+H].sup.+.
[0734] The following Intermediates were synthesized from the
appropriate amine and aldehyde Intermediates following the
procedures described for Intermediate 32.
TABLE-US-00022 Int Structure Name [M + H].sup.+ 32.01.sup.2
##STR00788## trans-N-(3-(3-Cyclopropylisothiazol-
5-yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-3-
methylphenyl)pyridin[2.2.2]
octan-1-yl)methyl)cyclohexanecarboxamide 585.4 32.02.sup.2
##STR00789## trans-N-(3-(2-Cyclopropyloxazol-4-
yl)phenyl)-4-hydroxy-N-(trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)cyclohexane- carboxamide 543.3
32.03.sup.2 ##STR00790## trans-N-(3-(2-Cyclopropyloxazol-4-
yl)phenyl)-N-((trans-4-(6- (dimethylamino)pyridine-3-
yl)cyclohexyl)methyl)-4- hydroxycyclohexanecarboxamide 543.5 32.04
##STR00791## trans-4-Hydroxy-N-(3-(2-isopropyloxazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 545.4
32.05.sup.2 ##STR00792## trans-4-Hydroxy-N-(3-(2-
isopropyloxazol-4-yl)phenyl)-N-
((trans-4-(5-methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 546.5 32.06.sup.2
##STR00793## trans-N-(3-(2-Cyclopropyloxazol-4-
yl)phenyl)-4-hydroxy-N-((trans-4-(5-
methoxy-6-methylpyridin-2-yl)cyclohexyl)
methyl)cyclohexanecarboxamide 544.4 32.07 ##STR00794##
trans-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridine-2-yl)-4-hydroxy-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide
544.4 32.08.sup.4 ##STR00795## trans-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridine-2-yl)-4-hydroxy-N-((trans-4-(5-
methoxy-6-methylpyridin-2-yl)cyclohexyl)
methyl)cyclohexanecarboxamide 545.9 32.09.sup.1,4,6 ##STR00796##
cis-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)-4-hydroxy-N-((4-(5-methoxy-
6-methylpyridin-2-yl)cyclohexyl)methyl) cyclohexanecarboxamide
545.3 32.10.sup.2 ##STR00797##
trans-N-((trans-4-(3-Cyano-4-methoxyphenyl)
cyclohexyl)methyl)-N-(3-(2-cyclopropyl- oxazol-4-yl)phenyl)-4-
hydroxycyclohexanecarboxamide 554.5 32.11.sup.2 ##STR00798##
trans-N-((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)-N-
(3-(2-cyclopropyloxazol-4-yl)phenyl)-4-
hydroxycyclohexanecarboxamide 555.5 32.12.sup.5 ##STR00799##
trans-N-(3-(6-(Dimethylamino)pyridin-3-
yl)phenyl)-4-hydroxy-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexanecarboxamide 557.5 32.13.sup.2,3
##STR00800## trans-4-Hydroxy-N-(4-(2-
isopropyloxazol-4-yl)pyridine-2-yl)-N-((trans-
4-(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)
cyclohexanecarboxamide 547.4 32.14.sup.2 ##STR00801##
trans-N-((trans-4-(6-Cyano-5- methoxpyridin-2-
yl)cyclohexyl)methyl)-4-hydroxy-N-(3-(2-
isopropyloxazol-4-yl)phenyl) cyclohexanecarboxamide 557.5 Alternate
conditions: Step 1: .sup.1Solvent was CH.sub.2Cl.sub.2; Step 2:
.sup.2Solvent was CH.sub.2Cl.sub.2; .sup.3Base was Et.sub.3N;
.sup.4DMAP, Et.sub.3N, toluene, 80 .degree.C.;
.sup.5trans-4-((tert-butyldimethyl- silyl)oxy)cyclohexanecarboxylic
acid, 1-propylphosphonic acid, cyclic anhydride (50 wt. % in
CH.sub.2Cl.sub.2), pyridine, rt, 200 min. .sup.6Synthesized from an
isomeric mixture of Intermediate 3.02.
Compound 1
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)-
pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate
##STR00802##
[0736] A mixture of Intermediate 29.15 (101 mg, 0.181 mmol), CDI
(59 mg, 0.364 mmol), and CH.sub.3CN (2 mL) was heated at 80.degree.
C. for 130 min, cooled to rt, and concentrated. Methylamine (40% in
CH.sub.3OH, 1.5 mL) was added to the reaction. The mixture was
stirred for 15 min, diluted with EtOAc (20 mL), washed (20 mL
H.sub.2O and then 20 mL brine), dried (Na.sub.2SO.sub.4), filtered
and then concentrated. The residue was purified by silica gel
chromatography (60-100% EtOAc in hexanes) to give
trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino-
)pyridin-3-ylcyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate
(103 mg, 93%) as a white foam. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.00 (d, 1H), 7.78 (d, 1H), 7.55-7.50 (m, 1H), 7.46 (t,
1H), 7.30-7.27 (m, 3H), 7.15-7.09 (m, 1H), 6.47 (d, 1H), 4.65-4.51
(m, 1H), 4.49-4.37 (m, 1H), 3.61 (d, 2H), 3.03 (s, 6H), 2.75 (d,
3H), 2.41-2.30 (m, 2H), 2.20-2.07 (m, 1H), 2.04-1.94 (m, 2H),
1.91-1.69 (m, 8H), 1.60-1.50 (m, 1H), 1.39-1.28 (m, 2H), 1.23-1.10
(m, 5H), 1.11-0.96 (m, 2H); LCMS: 616.5 [M+H].sup.+.
[0737] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 1.
TABLE-US-00023 Cmpd Structure Name [M + H].sup.+ 1.01 ##STR00803##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 616.5 1.02 ##STR00804##
4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((4-(6-(dimethylamino)pyridin-
3-yl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl trans-
methylcarbamate 642.4 1.03 ##STR00805##
trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(3-fluoro-1-methyl- 1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl) cyclohexyl methylcarbamate 644.3
1.04 ##STR00806## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methylcarbamate 599.5 1.05 ##STR00807##
4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- methylcarbamate 625.6 1.06.sup.1 ##STR00808##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl carbamate 585.5 1.07.sup.3 ##STR00809##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methyl carbonate 600.1 1.08.sup.2 ##STR00810##
4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- carbamate 611.4 1.09 ##STR00811##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(3-fluoro-1-methyl- 1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl) cyclohexyl methylcarbamate 627.6
1.10 ##STR00812## trans-4-((3-(1-Isopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexyl methylcarbamate 602.4
Alternate conditions: .sup.140% ammonia in CH.sub.3OH; .sup.20.4M
ammonia in THF then 40% ammonia in CH.sub.3OH; .sup.3Isolated
during the purification of Compound 1.06.
Compound 2
trans-4-((3-(3-Cyclopropylisothiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
methylcarbamate
##STR00813##
[0739] CDI (44.1 mg, 0.272 mmol) was added to a solution of
Intermediate 31 (101.3 mg, 0.181 mmol) in CH.sub.3CN (5 mL). The
reaction mixture was heated at 80.degree. C. overnight, allowed to
cool to rt, and then concentrated to give a colorless oil. This oil
was dissolved in CH.sub.2Cl.sub.2 (3 mL). Methylamine (2 M in THF,
1.10 mL) was added to the solution, and the reaction was stirred at
rt overnight. The reaction mixture was concentrated and purified by
reverse-phase HPLC [water(10 mM NH.sub.4HCO.sub.3)-CH.sub.3CN] to
obtain
trans-4-((3-(3-cyclopropylisothiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl methylcarbamate
(70 mg, 63% yield) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.61-7.55 (m, 1H), 7.52 (t, 1H), 7.38 (s, 1H),
7.22 (d, 1H), 7.15 (s, 1H), 6.99-6.93 (m, 2H), 6.74 (d, 1H), 4.57
(br s, 1H), 4.42 (s, 1H), 3.80 (s, 3H), 3.64 (d, 2H), 2.74 (d, 3H),
2.39 (t, 1H), 2.24-2.17 (m, 4H), 2.16-2.09 (m, 1H), 1.97-2.02 (m,
2H), 1.88 (d, 2H), 1.83-1.70 (m, 6H), 1.60-1.58 (m, 1H), 1.42-1.29
(m, 2H), 1.27-1.12 (m, 2H), 1.10-0.95 (m, 6H); LCMS: 616.3
[M+H].sup.+.
[0740] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 2.
TABLE-US-00024 Cmpd Structure Name [M + H].sup.+ 2.01 ##STR00814##
trans-4-(((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)(3-(2- methoxythiazol-5-
yl)phenyl)carbamoyl)cyclohexyl methylcarbamate 606.3 2.02
##STR00815## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexyl methylcarbamate 617.4
2.03 ##STR00816## 4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- methylcarbamate 643.5 2.04 ##STR00817##
trans-4-(((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)(3-
(thiazol-2- ylethynyl)phenyl)carbamoyl)cyclohexyl methylcarbamate
600.2 2.05 ##STR00818## 4-(((4-(4-Methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)(3-(thiazol-2-
ylethynyl)phenyl)carbamoyl)cyclohexyl trans-methylcarbamate 626.3
2.06 ##STR00819## trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl) methylcarbamate 600.3 2.07 ##STR00820##
4-((3-(2-Cyclopropyloxazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- methylcarbamate 626.5 2.08 ##STR00821##
4-((3-(3-Cyclopropylisothiazol-5- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl
trans- methylcarbamate 642.3
Compound 3
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)-
bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate
##STR00822##
[0742] A mixture of Intermediate 30.14 (81 mg, 0.14 mmol), CDI (46
mg, 0.29 mmol), and CH.sub.3CN (1.5 mL) was heated at 80.degree. C.
for 2 h, allowed to cool to rt, and then concentrated. The residue
was dissolved in CH.sub.2Cl.sub.2 (3 mL). A portion of this
solution (1.5 mL, 0.071 mmol) was concentrated and then diluted
with methylamine (40% in CH.sub.3OH, 1.5 mL). The mixture was
stirred at rt for 2 h, diluted with EtOAc (20 mL), washed (20 mL
H.sub.2O and then 20 mL brine), dried (Na.sub.2SO.sub.4), filtered,
concentrated, and then purified by silica gel chromatography (0-5%
CH.sub.3OH in CH.sub.2Cl.sub.2) to give
4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl-
)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl
trans-methylcarbamate (39 mg, 89%) as a white foam. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.53 (s, 1H), 7.96-7.94 (m, 1H),
7.74-7.67 (m, 2H), 7.48 (t, 1H), 7.40 (dd, 1H), 7.33 (d, 1H),
6.84-6.77 (m, 1H), 6.52 (d, 1H), 4.39-4.28 (m, 1H), 3.78-3.44 (m,
2H), 2.94 (s, 6H), 2.27-2.12 (m, 2H), 1.89-1.79 (m, 2H), 1.74-1.58
(m, 8H), 1.53-1.32 (m, 8H), 1.11-1.02 (m, 2H), 1.02-0.97 (m, 2H),
0.97-0.82 (m, 2H), NHCH.sub.3 under DMSO; LCMS: 626.5
[M+H].sup.+.
[0743] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 3.
TABLE-US-00025 Cmpd Structure Name [M + H].sup.+ 3.01.sup.1
##STR00823## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl ethylcarbamate 613.5 3.02 ##STR00824##
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl) cyclohexyl methylcarbamate 600.4
3.03 ##STR00825## 4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((4-(6- (dimethylamino)pyridin-3-
yl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl trans-
methylcarbamate 625.6 3.04 ##STR00826##
trans-4-((4-(1-Cyclopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl
methylcarbamate 600.5 3.05 ##STR00827##
trans-4-((3-(2-Cyclopropyloxazol-4- yl)phenyl)((trans-4-(6-
(dimethylamino)pyridine-3- yl)cyclohexyl)methyl)carbamoyl)
cyclohexyl methylcarbamate 600.4 .sup.12M ethylamine in THF.
Compound 4
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate
##STR00828##
[0745] A mixture of Intermediate 29.11 (130 mg, 0.240 mmol), CDI
(59 mg, 0.364 mmol), and CH.sub.3CN (2 mL) was heated at 80.degree.
C. for 2 h, allowed to cool to rt, and concentrated. The residue
was dissolved in CH.sub.2Cl.sub.2 (2 mL). Ethanolamine (149 mg,
2.44 mmol) was added to the reaction, and the mixture was stirred
for 40 min, diluted with EtOAc (20 mL), washed (20 mL H.sub.2O and
then 20 mL brine), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was purified by silica gel chromatography
(0-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give
trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
(2-hydroxyethyl)carbamate (131 mg, 87%) as a white foam. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.93 (s, 1H),
7.60 (d, 1H), 7.55 (s, 1H), 7.44 (t, 1H), 7.10 (d, 1H), 6.98-6.92
(m, 2H), 6.85 (t, 0.87H), 6.80-6.45 (m, 1H), 6.60-6.45 (m, 0.13H),
4.55 (t, 1H), 4.40-4.26 (m, 1H), 3.80-3.69 (m, 4H), 3.66-3.40 (m,
2H), 3.35-3.25 (m, 2H), 3.03-2.82 (m, 2H), 2.38-2.27 (m, 1H),
2.18-2.03 (m, 4H), 1.90-1.80 (m, 2H), 1.80-1.63 (m, 6H), 1.56-1.38
(m, 3H), 1.35-1.21 (m, 2H), 1.12-0.95 (m, 6H), 0.95-0.82 (m, 2H);
LCMS: 629.6 [M+H].sup.+.
[0746] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 4.
TABLE-US-00026 Cmpd Structure Name [M + H].sup.+ 4.01 ##STR00829##
trans-4-((3-(2-Cyclo- propylthiazol-5-yl)- phenyl)((trans-4-(4-
methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl
(2- hydroxyethyl)car- bamate 646.4 4.02 ##STR00830##
4-((3-(2-Cyclo- propylthiazol-5-yl)- phenyl)((4-(4-
methoxy-3-methyl- phenyl)bicyclo- [2.2.2]octan-1-yl)-
methyl)carbamoyl)- cyclohexyl (2- hydroxyethyl)trans- carbamate
672.5 4.03 ##STR00831## 4-((3-(2-Cyclo- propylthiazol-5-
yl)phenyl)((4-(6- (dimethylamino)- pyridin-3-yl)-
bicyclo[2.2.2]octan- 1-yl)methyl)car- bamoyl)cyclohexyl
(2-hydroxyethyl)- trans-carbamate 672.6 4.04 ##STR00832##
4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((4-(4-
methoxy-3-methyl- phenyl)bicyclo- [2.2.2]octan-1-yl)-
methyl)carbamoyl)- cyclohexyl (2- hydroxyethyl)trans- carbamate
655.7 4.05 ##STR00833## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl isopropylcarbamate 627.6 4.06
##STR00834## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-methoxyazetidine-
1-carboxylate 655.4 4.07 ##STR00835## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
morpholine-4-car- boxylate 655.5 4.08 ##STR00836##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl cyclopropylcarbamate 625.6 4.09 ##STR00837##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl (2-(dimethylamino)- ethyl)carbamate 656.5 4.10
##STR00838## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (3-hydroxypropyl)- carbamate
643.7 4.11 ##STR00839## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (3-(dimethylamino)-
propyl)carbamate 670.5 4.12 ##STR00840## 4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((4-(6- (dimethylamino)-
pyridin-3-yl)bicyclo- [2.2.2]octan-1-yl)- methyl)carbamoyl)-
cyclohexyl (2- hydroxyethyl)trans- carbamate 655.5 4.13
##STR00841## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl ((1H-imidazol-2-yl)-
methyl)carbamate 665.6 4.14 ##STR00842## tert-Butyl (2-((((trans-
4-((3-(1-cyclopropyl- 1H-pyrazol-4-yl)- phenyl)((trans-4-(4-
methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl)oxy)- carbonyl)amino)- 742.9 ethyl)(methyl)car- bamate
4.15.sup.1 ##STR00843## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl ((1H-imidazol-4-yl)-
methyl)carbamate 665.7 4.16 ##STR00844## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
(2-aminoethyl)car- bamate 628.4 4.17 ##STR00845## tert-Butyl
3-((((trans- 4-((3-(1-cyclopropyl- 1H-pyrazol-4-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl)oxy)car- bonyl)amino)azeti-
dine-1-carboxylate 740.6 4.18.sup.4 ##STR00846##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)- carbamoyl)cyclo-
hexyl azetidin-3- ylcarbamate 640.5 4.19 ##STR00847##
trans-4-((4-(1-Cyclo- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(4-methoxy- 3-methylphenyl)- cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl (2-hydroxy- ethyl)carbamate 630.5 4.20
##STR00848## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (4-(dimethylamino)-
butyl)carbamate 684.6 4.21 ##STR00849## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
(5-(dimethylamino)- pentyl)carbamate 698.7 4.22 ##STR00850##
trans-4-((3-(2-Cyclo- propyloxazol-4-yl)- phenyl)((trans-4-(6-
(dimethylamino)- pyridine-3-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate 630.4 4.23
##STR00851## 4-((3-(2-Cyclopropyl- oxazol-4-yl)phenyl)-
((4-(6-(dimethyl- amino)pyridin-3-yl)- bicyclo[2.2.2]octan-
1-yl)methyl)car- bamoyl)cyclohexyl trans-(2-hydroxy-
ethyl)carbamate 656.5 4.24 ##STR00852## trans-4-((4-(2-Cyclo-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclo- hexyl
(2-hydroxy- ethyl)carbamate 632.6 4.25.sup.2 ##STR00853##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 641.2
4.26.sup.2 ##STR00854## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl 3-hydroxy-
azetidine-1-carbox- ylate 642.4 4.27.sup.2 ##STR00855##
trans-4-((4-(1-Cyclo- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(4-methoxy- 3-methylphenyl)- cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl 3-hydroxy- azetidine-1-carbox- ylate 642.5
4.28.sup.3 ##STR00856## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-((methylthio)-
methyl)azetidine-1- carboxylate 685.7 Carbamate formation:
.sup.1CH.sub.3OH was added to help solubility; .sup.2iPr.sub.2NEt
was added because amine was an HCl salt; .sup.3Et.sub.3N was added
because amine was an HCl salt. .sup.4From deprotection of Compound
4.17 (20% TFA in CH.sub.2Cl.sub.2).
Compound 5
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopro-
pyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
ethylcarbamate
##STR00857##
[0748] A mixture of Intermediate 30.04 (520 mg, 0.936 mmol), CDI
(232 mg, 1.44 mmol), and CH.sub.3CN (13 mL) was heated at
80.degree. C. for 165 min. Additional CDI (16 mg, 0.099 mmol) was
added to the mixture, and the reaction was heated for 30 min and
then allowed to cool to rt. A portion of this solution (1 mL, 0.072
mmol) was added to ethylamine (2 M in THF, 1 mL, 2.0 mmol). The
mixture was stirred overnight, diluted with EtOAc (15 mL), washed
(15 mL H.sub.2O and then 15 mL brine), dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was purified by silica gel
chromatography (0-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give
trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1--
isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl
ethylcarbamate (41 mg, 91%) as a white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.55 (s, 1H), 8.43 (d, 1H), 8.14 (s, 1H),
7.66 (s, 1H), 7.56 (dd, 1H), 7.51 (d, 1H), 7.49 (dd, 1H), 7.11 (d,
1H), 6.92 (t, 0.87H), 6.70-6.55 (m, 0.13H), 4.52 (sept, 1H),
4.41-4.27 (m, 1H), 3.85 (s, 3H), 3.68 (d, 2H), 3.00-2.82 (m, 2H),
2.47-2.36 (m, 1H), 2.30-2.14 (m, 1H), 1.91-1.65 (m, 8H), 1.55-1.37
(m, 9H), 1.36-1.22 (m, 2H), 1.08-0.85 (m, 7H); LCMS: 627.5
[M+H].sup.+.
[0749] The Compounds below were synthesized using the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 5.
TABLE-US-00027 Cmpd Structure Name [M + H].sup.+ 5.01.sup.3
##STR00858## trans-4-((4-(2-Cyclo- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 617.5
5.02.sup.3 ##STR00859## trans-4-((4-(2-Iso- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 619.5
5.03.sup.3 ##STR00860## trans-4-((4-(2-Cyclo- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methylcarbamate 618.5
5.04.sup.2 ##STR00861## trans-4-((4-(2-Iso- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methylcarbamate 620.5
5.05.sup.2 ##STR00862## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(2-cyclo- propylthiazol-5-yl)-
pyridin-2-yl)car- bamoyl)cyclohexyl methylcarbamate 628.4
5.06.sup.2 ##STR00863## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(2- cyclopropylthiazol-
5-yl)phenyl)car- bamoyl)cyclohexyl methylcarbamate 628.5 5.07.sup.2
##STR00864## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(4-(2- cyclopropylthiazol-
5-yl)pyridin-2-yl)car- bamoyl)cyclohexyl methylcarbamate 629.6
5.08.sup.3 ##STR00865## trans-4-((3-(2-Iso- propylthiazol-5-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 619.5
5.09.sup.1,3 ##STR00866## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol-4- yl)phenyl)((trans-4- (6-(dimethylamino)-
pyridin-3-yl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
methylcarbamate 599.5 5.10.sup.3 ##STR00867## trans-4-((3-(1-Iso-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
methylcarbamate 601.6 5.11.sup.3 ##STR00868##
trans-4-(((trans-4-(5- Chloro-6-methoxy- pyridin-3-yl)cyclo-
hexyl)methyl)(3-(1- cyclopropyl-1H- pyrazol-4-yl)phenyl)-
carbamoyl)cyclohexyl methylcarbamate 620.4 5.12.sup.3 ##STR00869##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(4-methoxy- 3-methylphenyl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl methylcarbamate 602.5 5.13.sup.3 ##STR00870##
trans-4-((4-(1-Cyclo- propyl-1H-pyrazol-4- yl)pyridin-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl methylcar- bamate 601.5 5.14.sup.3
##STR00871## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(3-(1-cyclo- propyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)- cyclohexyl methyl- carbamate 610.5 5.15.sup.3
##STR00872## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(3-(1-Iso- propyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)- cyclohexyl methyl- carbamate 612.3 5.16.sup.3
##STR00873## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(6- methoxy-5-methyl- pyridin-3-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 600.5
5.17.sup.3 ##STR00874## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-cyclo- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)- carbamoyl)cyclohexyl methylcarbamate 611.5
5.18.sup.3 ##STR00875## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)- carbamoyl)cyclohexyl methylcarbamate 613.5
5.19.sup.2 ##STR00876## cis-4-(((4-(3-Cyano-4- methoxyphenyl)cyclo-
hexyl)methyl)(4-(1- isopropyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
carbamoyl)cyclohexyl methylcarbamate 613.7 5.20.sup.2 ##STR00877##
trans-4-((3-(1-(tert- Butyl)-1H-pyrazol-4- yl)phenyl)((trans-4-
(5-methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl methylcarbamate 616.6 5.21.sup.2 ##STR00878##
trans-4-((3-(1-Cyclo- butyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(5-methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl methylcarbamate 614.5 5.22.sup.2 ##STR00879##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl dimethyl- carbamate 613.5 5.23.sup.2 ##STR00880##
trans-4-(((trans-4-(6- Cyano-5-methoxy- pyridin-2-yl)cyclo-
hexyl)methyl)(3-(1- cyclopropyl-1H- pyrazol-4-yl)phenyl)-
carbamoyl)cyclohexyl methylcarbamate 611.5 5.24.sup.2 ##STR00881##
trans-4-((4-(1-Iso- propyl-1H-pyrazol-4- yl)pyridin-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl methylcarbamate 603.5 5.25 ##STR00882##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)methyl)-
carbamoyl)cyclohexyl ethylcarbamate 617.6 5.26.sup.2 ##STR00883##
trans-4-(((trans-4-(6- Cyano-5-methoxy- pyridin-2-yl)cyclo-
hexyl)methyl)(4-(1- isopropyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
carbamoyl)cyclohexyl methylcarbamate 614.5 5.27.sup.2 ##STR00884##
trans-4-(((trans-4-(6- Cyano-5-methoxy- pyridin-2-yl)cyclo-
hexyl)methyl)(4-(1- cyclopropyl-1H- pyrazol-4-yl)pyridin-
2-yl)carbamoyl)- cyclohexyl methyl- carbamate 612.5 5.28.sup.2
##STR00885## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3- (1-isopropyl-1H-
pyrazol-4-yl)phenyl)- carbamoyl)cyclohexyl methylcarbamate 613.6
5.29.sup.5 ##STR00886## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(4-(1- isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)- carbamoyl)cyclohexyl ethylcarbamate 628.5
5.30.sup.3 ##STR00887## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl methyl- carbamate 602.5 5.31.sup.3
##STR00888## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 603.3
5.32.sup.3 ##STR00889## trans-4-((3-(2-Cyclo- propyloxazol-4-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 601.5
5.33.sup.3 ##STR00890## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 601.5
5.34.sup.3 ##STR00891## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methylcarbamate 602.5
5.35.sup.3 ##STR00892## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(3-(2-cyclo- propyloxazol-4-yl)-
phenyl)carbamoyl)- cyclohexyl methyl- carbamate 611.5 5.36.sup.2
##STR00893## trans-4-((3-(6- (Dimethylamino)-
pyridine-3-yl)phenyl)- ((trans-4-(4-methoxy- 3-methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 613.6
5.37.sup.2 ##STR00894## trans-4-((3-(6-Cyclo- propylpyridin-3-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl methyl- carbamate 610.5 5.38.sup.2
##STR00895## trans-4-((3-(2- (Dimethylamino)- pyrimidin-5-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl methyl- carbamate 614.6 5.39.sup.2
##STR00896## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(2-cyclo- propyloxazol-4-yl)-
pyridine-2-yl)car- bamoyl)cyclohexyl methylcarbamate 612.5
5.40.sup.2 ##STR00897## trans-4-((6-(Dimethyl-
amino)-[3,4'-bipyridin]- 2'-yl)((trans-4-(4- methoxy-3-methyl-
phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl methyl- carbamate
614.5 5.41.sup.2 ##STR00898## trans-4-((3-(6- ((Dimethylamino)-
pyridine-3-yl)phenyl)- ((trans-4-(5-methoxy- 6-methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methylcarbamate 614.5
5.42.sup.2 ##STR00899## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(2- cyclopropyloxazol-
4-yl)phenyl)car- bamoyl)cyclohexyl methylcarbamate 612.7 5.43.sup.2
##STR00900## trans-4-((4-(2-Iso- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methylcarbamate 604.5
5.44.sup.2 ##STR00901## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(4-(2- cyclopropyloxazol-4-
yl)pyridine-2-yl)car- bamoyl)cyclohexyl methylcarbamate 613.5
5.45.sup.2 ##STR00902## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(2-iso- propyloxazol-4-yl)-
pyridine-2-yl)car- bamoyl)cyclohexyl methylcarbamate 614.5
5.46.sup.2 ##STR00903## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(2- isopropyloxazol-4-
yl)phenyl)carbamoyl)- cyclohexyl methyl- carbamate 614.4 5.47
##STR00904## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl ethylcarbamate 616.5
5.48.sup.4 ##STR00905## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl carbamate 588.4 5.49.sup.6
##STR00906## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methyl carbonate 603.4
5.50.sup.2 ##STR00907## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(6-methoxy-5- methylpyridin-3-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl methylcarbamate 602.4
5.51.sup.2 ##STR00908## trans-4-((4-(2-Ethyl- oxazol-4-yl)pyridin-
2-yl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl methylcarbamate 590.5
5.52.sup.2 ##STR00909## trans-4-((3-(1-Iso- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)-1-methyl- cyclohexyl methyl- carbamate
615.4 5.53.sup.2 ##STR00910## cis-4-((3-(1-Isopropyl-
1H-pyrazol-4-yl)- phenyl)(trans-4-(4- methoxy-3-methyl-
phenyl)cyclohexyl)- methyl)carbamoyl)- 1-methylcyclohexyl
methylcarbamate 615.5 Acyl-imidazole formation: .sup.1DMF as
solvent. Carbamate formation: .sup.22M methylamine in THF;
.sup.340% methylamine in CH.sub.3OH; .sup.47M ammonia in
CH.sub.3OH; .sup.5Stirred at rt for 4 h, heated at 80.degree. C.
for 1 h, and then stirred at rt for 1 h. .sup.6Isolated during the
purification of Compound 5.48.
Compound
trans-4-((4-(2-Isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6-m-
ethylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate
##STR00911##
[0751] Intermediate 32.13 (98 mg, 0.18 mmol) and CDI (45 mg, 0.28
mmol) were dissolved in CH.sub.3CN (2 mL). The reaction was heated
at 80.degree. C. for 15.5 h. Additional CDI (11 mg, 0.068 mmol) was
added at rt. The reaction was heated at 80.degree. C. for 1 h and
then allowed to cool to rt. A portion of the reaction (1 mL, 0.090
mmol) was added to morpholine (80 .mu.L, 0.915 mmol). The reaction
was stirred at rt for 72 h and then diluted with EtOAc (20 mL). The
organics were washed with water (20 mL), washed with brine (20 mL),
dried (Na.sub.2SO.sub.4), filtered, concentrated, and then purified
by silica gel chromatography (0-5% CH.sub.3OH in CH.sub.2Cl.sub.2)
to give
trans-4-((4-(2-isopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6--
methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
morpholine-4-carboxylate (52 mg, 88% yield) as an off-white foam.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.85 (s, 1H), 8.55 (d,
1H), 7.71 (s, 1H), 7.70 (d, 1H), 7.18 (d, 1H), 6.97 (d, 1H),
4.48-4.38 (m, 1H), 3.80 (s, 3H), 3.73-3.65 (m, 2H), 3.58-3.42 (m,
4H), 3.30-3.22 (m, 4H), 3.22-3.12 (m, 1H), 2.50-2.42 (m, 1H), 2.28
(s, 3H), 2.28-2.20 (m, 1H), 1.96-1.85 (m, 2H), 1.85-1.72 (m, 6H),
1.58-1.42 (m, 3H), 1.41-1.26 (m, 8H), 1.12-0.96 (m, 4H); LCMS:
660.6 [M+H].sup.+.
[0752] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 6.
TABLE-US-00028 Cmpd Structure Name [M + H].sup.+ 6.01.sup.1
##STR00912## 4-((3-(2-Cyclopropyl- thiazol-5-yl)phenyl)-
((trans-4-(6-dimethyl- amino)pyridin-3-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl (2-hydroxyethyl)- trans-carbamate 646.5 6.02
##STR00913## trans-4-((4-(2-Cyclo- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(4-methoxy-3- methylphenyl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl (2-hydroxy-
ethyl)carbamate 647.5 6.03 ##STR00914## trans-4-((4-(2-Iso-
propylthiazol-5-yl)- pyridin-2-yl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
(2-hydroxyethyl)- carbamate 649.6 6.04 ##STR00915##
trans-4-((3-(2-Iso- propylthiazol-5-yl)- phenyl)((trans-4-(5-
methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate 649.6 6.05
##STR00916## trans-4-((3-(2-Iso- propylthiazol-5-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (3-hydroxypropyl)- carbamate
663.5 6.06 ##STR00917## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(2- cyclopropylthiazol-
5-yl)phenyl)car- bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate
658.6 6.07 ##STR00918## trans-4-((3-(2-Cyclo- propylthiazol-5-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate
647.5 6.08.sup.1 ##STR00919## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol-4- yl)phenyl)((trans-4- (6-(dimethylamino)-
pyridin-3-yl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
(2-hydroxyethyl)- carbamate 629.5 6.09 ##STR00920##
trans-4-((3-(1-Isopro- pyl-1H-pyrazol-4-yl)- phenyl)((trans-4-(4-
methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl
(2- hydroxyethyl)car- bamate 631.5 6.10.sup.2 ##STR00921##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl (2- methoxyethyl)car- bamate 643.5 6.11 ##STR00922##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl (1,3- dihydroxypropan- 2-yl)carbamate 659.5 6.12
##STR00923## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (4-methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl ((S)-2,3- dihydroxypropyl)car- bamate
659.5 6.13 ##STR00924## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (4-methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl ((R)-2,3- dihydroxypropyl)- carbamate
659.7 6.14 ##STR00925## trans-4-((3-(1-Iso- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (4-methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl (3- hydroxypropyl)- carbamate 645.4
6.15 ##STR00926## trans-4-((3-(1-Iso- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (2- hydroxyethyl)-
carbamate 632.5 6.16 ##STR00927## trans-4-((3-(1-Iso-
propyl-1H-pyrazol-4- yl)phenyl)((trans-4- (5-methoxy-6-
methylpyridin-2- yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (3-
hydroxypropyl)- carbamate 646.5 6.17 ##STR00928##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(4-methoxy- 3-methylphenyl)- cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl (2-hydroxy- ethyl)carbamate 632.5 6.18
##STR00929## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (1-methylazetidin-
3-yl)carbamate 654.5 6.19 ##STR00930## trans-4-(((trans-4-(3-
Cyano-4-methoxy- phenyl)cyclohexyl)- methyl)(3-(1-cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)car- bamoyl)cyclohexyl
(2-hydroxyethyl)- carbamate 662.5 M + Na 6.20 ##STR00931##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(3-(1-iso- propyl-1H-pyrazol- 4-yl)phenyl)car-
bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate 642.6 6.21
##STR00932## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-cyclo- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)car- bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate
641.5 6.22 ##STR00933## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)car- bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate
643.5 6.23 ##STR00934## trans-4-(((trans-4-(5- Chloro-6-methoxy-
pyridin-3-yl)cyclo- hexyl)methyl)(3-(1- cyclopropyl-1H-
pyrazol-4-yl)phenyl)- carbamoyl)cyclohexyl (2-hydroxyethyl)-
carbamate 650.3 6.24 ##STR00935## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
oxetan-3-ylcarbamate 641.6 6.25 ##STR00936## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans-4- (4-methoxy-3-methyl-
phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 4-methyl-
piperazine-1-carbox- ylate 668.5 6.26 ##STR00937##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl (2- methoxyethyl)- (methyl)carbamate 679.6 M + Na 6.27
##STR00938## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl thiomorpholine-4- carboxylate
671.5 6.28 ##STR00939## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(1- cyclopropyl-1H-
pyrazol-4-yl)phenyl)- carbamoyl)cyclo- hexyl (2-hydroxy-
ethyl)carbamate 641.7 6.29 ##STR00940## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol-4- yl)phenyl)((trans-4- (4-methoxy-3-methyl-
phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 3-(methyl-
sulfonyl)azetidine-1- carboxylate 703.6 6.30 ##STR00941##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl 3-(methyl- thio)azetidine-1- carboxylate 671.5 6.31
##STR00942## trans-4-((4-(1-Iso- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl cyclo-
propylcarbamate 629.6 6.32 ##STR00943## trans-4-(((trans-4-(6-
Cyano-5-methoxy- pyridin-2-yl)cyclo- hexyl)methyl)(4-
(1-isopropyl-1H- pyrazol-4-yl)pyridin- 2-yl)carbamoyl)- cyclohexyl
iso- propylcarbamate 642.6 6.33 ##STR00944## trans-4-(((trans-4-(6-
Cyano-5-methoxy- pyridin-2-yl)cyclo- hexyl)methyl)(4-(1-
isopropyl-1H- pyrazol-4-yl)pyridin- 2-yl)carbamoyl)- cyclohexyl
cyclo- propylcarbamate 640.6 6.34 ##STR00945##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(1-iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)car-
bamoyl)cyclohexyl (2-methoxyethyl)- carbamate 657.5 6.35
##STR00946## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)car- bamoyl)cyclohexyl cyclopropylcarbamate 639.6
6.36 ##STR00947## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)car- bamoyl)cyclohexyl 3-(methylsulfonyl)-
azetidine-1-carbox- ylate 717.5 6.37 ##STR00948##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(1-iso- propyl-1H-pyrazol-4- yl)pyridin-2-yl)car-
bamoyl)cyclohexyl morpholine-4-carbox- ylate 669.6 6.38
##STR00949## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)car- bamoyl)cyclohexyl 4-methylpiperazine-
1-carboxylate 682.5 6.39 ##STR00950## trans-4-((4-(1-Iso-
propyl-1H-pyrazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy-
6-methylpyridin-2- yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 3-
(methylsulfonyl)- azetidine-1-carbox- ylate 707.5 6.40 ##STR00951##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl morph- oline-4-carboxylate 659.5 6.41
##STR00952## trans-4-((4-(1-Iso- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 4-
methylpiperazine- 1-carboxylate 672.5 6.42 ##STR00953##
trans-4-((3-(1-Iso- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(5-methoxy-6- methylpyridin-2- yl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl-3- (methylsulfonyl)- azetidine-1-carbox- ylate 706.3
6.43 ##STR00954## trans-4-((3-(1-Iso- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexylmorpholine-4-
carboxylate 658.4 6.44 ##STR00955## trans-4-((3-(1-Iso-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(5-methoxy-6-
methylpyridin-2- yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl
4-methyl- piperazine-1-carbox- ylate 671.4 6.45 ##STR00956##
4-((3-(2-Cyclopropyl- oxazol-4-yl)phenyl)- ((4-(4-methoxy-3-
methylphenyl)- bicyclo[2.2.2]octan- 1-yl)methyl)car-
bamoyl)cyclohexyl trans-(2-hydroxy- ethyl)carbamate 656.7
6.46.sup.1 ##STR00957## trans-4-((3-(2-Cyclo- propyloxazol-4-yl)-
phenyl)(trans-4-(4- methoxy-3-methyl phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl (2- hydroxyethyl)car- bamate 630.7
6.47 ##STR00958## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl (2- hydroxyethyl)car- bamate 632.4
6.48 ##STR00959## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (2-hydromethyl)car- bamate
633.6 6.49 ##STR00960## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (3-hydroxypropyl)- carbamate
647.6 6.50 ##STR00961## trans-4-((3-(2-Cyclo- propyloxazol-4-yl)-
phenyl)((trans-4- (5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl (2-hydroxy-
ethyl)carbamate 631.5 6.51 ##STR00962## trans-4-((3-(2-
Cyclopropyloxazol- 4-yl)phenyl)((trans- 4-(5-methoxy-6-
methylpyridin-2- yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (3-
hydroxypropyl)car- bamate 645.5 6.52 ##STR00963## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- ((trans-4-(4-meth-
oxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (2-
hydroxyethyl)car- bamate 631.6 6.53 ##STR00964##
trans-4-(((trans-4- (3-Cyano-4- methoxyphenyl)- cyclohexyl)methyl)-
(3-(2-cyclopropyl- oxazol-4-yl)phenyl)- carbamoyl)cyclo- hexyl
(2-hydroxy- ethyl)carbamate 641.6 6.54 ##STR00965##
trans-4-(((trans-4- (3-Cyano-4-meth- oxyphenyl)cyclo-
hexyl)methyl)(4-(2- cyclopropyloxazol- 4-yl)pyridine-2-yl)-
carbamoyl)cyclo- hexyl (2-hydroxy- ethyl)carbamate 642.6 6.55
##STR00966## trans-4-(((trans-4- (6-Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(2- cyclopropyloxazol-
4-yl)phenyl)car- bamoyl)cyclohexyl (2-hydroxyethyl)- carbamate
642.4 6.56 ##STR00967## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridine-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (2-meth-
oxyethyl)carbamate 646.5 6.57 ##STR00968## trans-4-((4-(2-
Cyclopropyloxazol-
4-yl)pyridine-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl cyclo-
propylcarbamate 628.5 6.58 ##STR00969## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- ((trans-4-(5-meth-
oxy-6-methylpyridin- 2-yl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl isopropyl- carbamate 630.6 6.59 ##STR00970##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridine-2-yl)-
((trans-4-(5-meth- oxy-6-methylpyridin- 2-yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl morph- oline-4-carboxylate 658.6 6.60
##STR00971## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridine-2-yl)- ((trans-4-(5-meth- oxy-6-methyl-
pyridin-2-yl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
oxetan-3-ylcarbamate 644.6 6.61 ##STR00972## trans-N-(4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- N-((trans-4-(5-
methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)-4-(2-
(3-(methylsulfonyl)- azetidin-1-yl)-2- oxoethyl)cyclo-
hexanecarboxamide 706.6 6.62 ##STR00973## trans-N-(4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- 4-(2-((3-hydroxy-
propyl)amino)-2- oxoethyl)-N-((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- cyclohexanecarbox- 646.5
amide 6.63 ##STR00974## trans-N-(4-(2- Cyclopropyloxazol-
4-yl)pyridine-2-yl)- N-((trans-4-(5- methoxy-6-methyl-
pyridin-2-yl)cyclo- hexyl)methyl)-4-(2- ((2-methoxyethyl)-
(methyl)amino)-2- oxoethyl)cyclo- 660.4 hexanecarboxamide 6.64
##STR00975## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridine-2-yl)- ((trans-4-(4-methoxy- 3-methylphenyl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl 4-methyl-
piperazine-1-car- boxylate 670.6 6.65 ##STR00976## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- ((trans-4-(5-methoxy-
6-methylpyridin-2- yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl
4-methyl- piperazine-1-carbox- ylate 671.6 6.66 ##STR00977##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridine-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)meth-
yl)carbamoyl)cyclo- hexyl ((S)-2,3- dihydroxypropyl)- carbamate
662.5 6.67 ##STR00978## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy- 6-methylpyridin-2-
yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl (2-hydroxy-
propyl)(methyl)car- bamate 660.4 6.68 ##STR00979## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-meth-
oxy-6-methylpyridin- 2-yl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl (2- hydroxy-2,3- dimethylbutyl)car- bamate 688.6 6.69
##STR00980## trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)meth-
yl)carbamoyl)cyclo- hexyl (2-hydroxy-2- methylbutyl)car- bamate
674.5 6.70 ##STR00981## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-meth- oxy-6-methyl-
pyridin-2-yl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
(2-hydroxy-2-methyl- propyl)carbamate 660.5 6.71 ##STR00982##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)meth-
yl)carbamoyl)cyclo- hexyl (1-hydroxy- propan-2-yl)car- bamate 646.6
6.72 ##STR00983## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy- 6-methylpyridin-2-
yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl (2-hydroxy-
propyl)carbamate 646.7 6.73 ##STR00984## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy-
6-methylpyridin-2- yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl
(3-hydroxy- butan-2-yl)carbamate 660.5 6.74 ##STR00985##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methylpyridin- 2-yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl ethyl(2- hydroxyethyl)car- bamate
660.6 6.75 ##STR00986## trans-4-((4-(2-Iso- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl 3-(methyl-
sulfonyl)azetidine- 1-carboxylate 708.3 6.76 ##STR00987##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridine-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)meth-
yl)carbamoyl)cyclo- hexyl 3-(2-hydroxy- ethoxy)azetidine-1-
carboxylate 688.5 6.77 ##STR00988## trans-4-((4-(2-
Isopropyloxazol-4- yl)pyridine-2-yl)- ((trans-4-(5-meth-
oxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 4-methylpiperazine- 1-carboxylate 673.5
6.78.sup.3 ##STR00989## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridine-2- yl)((trans-4-(5- methoxy-6-methyl-
pyridin-2-yl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
piperazine-1-carbox- ylate 657.3 6.79 ##STR00990## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- ((trans-4-(5-meth-
oxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl (1-methylpiperidin- 4-yl)carbamate 685.3 6.80
##STR00991## trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methylpyridin- 2-yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl ((R)-1- methylpiperidin-3-
yl)carbamate 685.5 6.81 ##STR00992## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridine-2-yl)- ((trans-4-(5-meth-
oxy-6-methylpyridin- 2-yl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl 4-ethyl- piperazine-1-carbox- ylate 685.5 6.82
##STR00993## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridine-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 4-iso-
propylpiperazine-1- carboxylate 699.5 6.83 ##STR00994##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 2,2-dimethylmorpho-
line-4-carboxylate 686.8 6.84 ##STR00995## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-meth-
oxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-(oxelan-3-yl)- azetidine-1-carbox- ylate 684.6
6.85 ##STR00996## trans-4-((4-(2- Ethyloxazo-4-yl)-
pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl (2-hydroxy-
ethyl)carbamate 620.4 6.86 ##STR00997## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-meth-
oxy-6-methylpyridin- 2-yl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl (2- hydroxy-2-methyl- propyl)(methyl)car- bamate 674.6
6.87 ##STR00998## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (2-
hydroxyethyl)(meth- yl)carbamate 646.5 6.88 ##STR00999##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methylpyridin- 2-yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl (3- hydroxypentan-2- yl)carbamate
674.5 6.89 ##STR01000## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy- 6-methylpyridin-2-
yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl (2- hydroxy-3-methyl-
butyl)carbamate 674.5 6.90 ##STR01001## trans-4-((4-(2-
Cyclopropyloxazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy-
6-methylpyridin-2- yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl
(1-hydroxy-2- methylpropan-2-yl)- carbamate 660.7 6.91 ##STR01002##
trans-4-((4-(2- Isopropyloxazol-4- yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl (2-hydroxy-2- methylpropyl)car-
bamate 662.4 6.92 ##STR01003## trans-4-((4-(1-Iso-
propyl-1H-pyrazol- 4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy-
6-methylpyridin-2- yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl
(2-hydroxy-2- methylpropyl)car- bamate 661.5 6.93 ##STR01004##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methylpyridin- 2-yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl ((S)-1- hydroxypropan-2- yl)carbamate
646.7 6.94 ##STR01005## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl ((R)-1-
hydroxypropan-2- yl)carbamate 646.7 6.95 ##STR01006##
trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-meth- oxy-6-methylpyridin- 2-yl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl ((R)-2- hydroxypropyl)car- bamate
646.7 6.96 ##STR01007## trans-4-((4-(2- Cyclopropyloxazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-meth- oxy-6-methylpyridin-
2-yl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl ((S)-2-
hydroxypropyl)car- bamate 646.6 Acyl-imidazole formation: .sup.1DMF
as solvent. Carbamate formation: Reactions that progressed slowly
at rt were either allowed to stir for multiple days or heated
(50-80.degree. C.); .sup.2Reaction was diluted with
CH.sub.2Cl.sub.2 prior to amine addition. .sup.3From
N-Boc-piperazine after deprotection (20% TFA in
CH.sub.2Cl.sub.2).
Compound 7
trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-methoxy-6-
-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate
##STR01008##
[0754] A mixture of Intermediate 32.08 (510 mg, 0.937 mmol), CDI
(233 mg, 1.44 mmol), and CH.sub.3CN (8 mL) was heated at 80.degree.
C. for 16 h and allowed to cool to rt. Diisopropylethylamine (1.5
mL, 8.6 mmol) and then azetidine-3-ol hydrochloride (465 mg, 4.24
mmol) were added to the reaction mixture at rt. The mixture was
stirred for 70 min, diluted with EtOAc (50 mL), washed (50 mL
H.sub.2O and then 50 mL brine), dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The residue was purified by silica gel
chromatography (0-7% CH.sub.3OH in CH.sub.2Cl.sub.2) to give
trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridine-2-yl)((trans-4-(5-met-
hoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-hydroxyazetidine-1-carboxylate (567 mg, 92%) as a white foam.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.77 (s, 1H), 8.54 (d,
2H), 7.71 (s, 1H), 7.67 (d, 1H), 7.19 (d, 1H), 6.97 (d, 1H), 5.63
(d, 1H), 4.41-4.31 (m, 2H), 4.01-3.94 (m, 2H), 3.74 (s, 3H),
3.73-3.67 (m, 2H), 3.60-3.53 (m, 2H), 2.50-2.42 (m, 1H), 2.28 (s,
3H), 2.26-2.17 (m, 1H), 1.90-1.72 (m, 8H), 1.55-1.40 (m, 3H),
1.40-1.27 (m, 2H), 1.13-0.94 (m, 8H); LCMS: 644.6 [M+H].sup.+.
[0755] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate amine following the procedure
described for Compound 7.
TABLE-US-00029 Cmpd Structure Name [M + H].sup.+ 7.01 ##STR01009##
trans-4-((3-(2-Cyclo- propylthiazol-5-yl)- phenyl)((trans-4-(6-
(dimethylamino)- pyridin-3-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 658.5
7.02.sup.1 ##STR01010## trans-4-((3-(2-Cyclo- propylthiazol-5-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl 3-hydroxy- azetidine-1-carbox- ylate
658.4 7.03 ##STR01011## trans-4-((4-(2-Cyclo- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-hydroxyazetidine-
1-carboxylate 659.5 7.04 ##STR01012## trans-4-((4-(2-Iso-
propylthiazol-5-yl)- pyridin-2-yl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 661.6 7.05 ##STR01013##
trans-4-((3-(2-Iso- propylthiazol-5-yl)- phenyl)((trans-4-(5-
methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 661.4 7.06
##STR01014## trans-4-((4-(2-Cyclo- propylthiazol-5-yl)-
pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-hydroxyazetidine-
l-carboxylate 660.6 7.07 ##STR01015## trans-4-((4-(2-Iso-
propylthiazol-5-yl)- pyridin-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 662.5 7.08 ##STR01016##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(2-cyclo- propylthiazol-5-yl)- pyridin-2-yl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 670.5 7.09
##STR01017## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(3-(2- cyclopropylthiazol-
5-yl)phenyl)car- bamoyl)cyclohexyl 3-hydroxazetidine- 1-carboxylate
670.5 7.10 ##STR01018## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(4-(2- cyclopropylthiazol-
5-yl)pyridin-2-yl)- carbamoyl)cyclo- hexyl 3-hydroxy-
azetidine-1-carbox- ylate 671.5 7.11 ##STR01019##
trans-4-((3-(2-Cyclo- propylthiazol-5-yl)- phenyl)((trans-4-(5-
methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 659.5
7.12.sup.1 ##STR01020## 4-((3-(1-Cyclopropyl- 1H-pyrazol-4-yl)-
phenyl)((4-(4-meth- oxy-3-methylphenyl)- bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)- cyclohexyl trans-3- hydroxyazetidine-1-
carboxylate 667.3 7.13 ##STR01021## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(6-(dimethyl-
amino)pyridin-3-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 641.5 7.14 ##STR01022##
trans-4-((3-(1-Iso- propyl-1H-pyrazol- 4-yl)phenyl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 643.4 7.15
##STR01023## trans-4-((3-(1-Iso- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-hydroxyazetidine-
1-carboxylate 644.5 7.16 ##STR01024## trans-4-((4-(1-Iso-
propyl-1H-pyrazol- 4-yl)pyridin-2-yl)- ((trans-4-(4-methoxy-
3-methylphenyl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 644.5 7.17 ##STR01025## Methyl
2-((((trans-4- ((3-(1-cyclopropyl- 1H-pyrazol-4-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl)oxy)car- bonyl)amino)acetate 657.7
7.18.sup.5 ##STR01026## 2-((((trans-4-((3-(1- Cyclopropyl-1H-
pyrazol-4-yl)phenyl)- ((trans-4-(4-methoxy- 3-methylphenyl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl)oxy)carbonyl)-
amino)acetic acid 643.5 7.19 ##STR01027## trans-4-(((trans-4-(3-
Cyano-4-methoxy- phenyl)cyclohexyl)- methyl)(3-(1-cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 674.4 M + Na 7.20 ##STR01028##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(3-(1-iso- propyl-1H-pyrazol- 4-yl)phenyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 654.5 7.21
##STR01029## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-1-cyclo- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)car- bamoyl)cyclohexyl 3-hydroxyazetidine-
1-carboxylate 653.5 7.22 ##STR01030## trans-4-(((trans-4-(3-
Cyano-4-methoxy- phenyl)cyclohexyl)- methyl)(4-(1-iso-
propyl-1H-pyrazol-4- yl)pyridin-2-yl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 655.5 7.23 ##STR01031##
trans-4-(((trans-4-(5- Chloro-6-methoxy- pyridin-3-yl)cyclo-
hexyl)methyl)(3-(1- cyclopropyl-1H- pyrazol-4-yl)phenyl)-
carbamoyl)cyclohexyl 3-hydroxyazetidin-1- carboxylate 662.4 7.24
##STR01032## trans-4-((4-(1-Cyclo- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)- ((trans-4-(5-methoxy- 6-methylpyridin-2-
yl)cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-hydroxyazetidine-1-
carboxylate 643.6 7.25 ##STR01033## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(6-methoxy-5-
methylpyridin-3-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 642.6 7.26 ##STR01034##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)(phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl 3-(meth- oxymethyl)azetidine- 1-carboxylate 669.6
7.27.sup.3 ##STR01035## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (4-methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl 3-(dimeth- ylamino)azetidine-1-
carboxylate 668.6 7.28 ##STR01036## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
3-(hydroxymethyl)- azetidine-1-carbox- ylate 655.6 7.29
##STR01037## trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-
4-yl)phenyl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl thiomorpholine-4- carboxylate
1-oxide 687.7 7.30 ##STR01038## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
thiomorpholine-4- carboxylate 1,1- dioxide 703.6 7.31 ##STR01039##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl azetidine- 1-carboxylate 625.6 7.32 ##STR01040##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol- 4-yl)phenyl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-((dimethylamino)- methyl)azetidine-1-
carboxylate 682.5 7.33 ##STR01041## trans-4-(((trans-4-(6-
Cyano-5-methoxy- pyridin-2-yl)cyclo- hexyl)methyl)(3-(1-
cyclopropyl-1H- pyrazol-4-yl)phenyl)- carbamoyl)cyclo- hexyl
3-hydroxy- azetidine-1-carbox- ylate 653.4 7.34 ##STR01042##
1-(trans-4-((3-(1- Cyclopropyl-1H- pyrazol-4-yl)phenyl)-
((trans-4-(4-methoxy- 3-methylphenyl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl) 3-methyl azetidine- 1,3-dicarboxylate 683.4
7.35.sup.5 ##STR01043## 1-(((trans-4-((3-(1- Cyclopropyl-1H-
pyrazol-4-yl)phenyl)- ((trans-4-(4-methoxy- 3-methylphenyl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl)oxy)carbonyl)-
azetidine-3-carboxylic acid 669.5 7.36 ##STR01044##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl 3-((tert- butoxycarbonyl)(meth- yl)amino)azetidine-1-
754.1 carboxylate 7.37.sup.6 ##STR01045## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol-4- yl)phenyl)((trans-4- (4-methoxy-3-methyl-
phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 3-(methyl-
amino)azetidine-1- carboxylate 654.7 7.38 ##STR01046##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl 3-((tert- butoxycarbonyl)- amino)azetidine-1-
carboxylate 762.6 M + Na 7.39.sup.6 ##STR01047##
trans-4-((3-(1-Cyclo- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(4-methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)-
cyclohexyl 3-amino- azetidine-1-carbox- ylate 640.6 7.40
##STR01048## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(4-(1- isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)car- bamoyl)cyclohexyl 3- hydroxyazetidine-1-
carboxylate 656.5 7.41.sup.2 ##STR01049## trans-4-((3-(1-Cyclo-
propyl-1H-pyrazol- 4-yl)phenyl)((trans-4- (4-methoxy-3-methyl-
phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl 3-(2-
methoxy-2-oxoethyl)- azetidine-1-carboxylate 697.8 7.42.sup.5
##STR01050## 2-(1-(((trans-4-((3-(1- Cyclopropyl-1H-
pyrazol-4-yl)phenyl)- ((trans-4-(4-methoxy- 3-methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl)- oxy)carbonyl)azetidin-
3-yl)acetic acid 683.8 7.43 ##STR01051## trans-4-(((trans-4-(6-
Cyano-5-methoxy- pyridin-2-yl)cyclo- hexyl)methyl)(3-(1-
isopropyl-1H-pyrazol- 4-yl)phenyl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 655.7 7.44 ##STR01052##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl isopropylcarbamate 631.6 7.45 ##STR01053##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(1-iso- propyl-1H-pyrazol-4- yl)pyridin-2-yl)car-
bamoyl)cyclohexyl dimethylcarbamate 627.6 7.46 ##STR01054##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(1-iso- propyl-1H-pyrazol-4- yl)pyridin-2-yl)car-
bamoyl)cyclohexyl azetidine-1-carbox- ylate 639.5 7.47 ##STR01055##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(1-iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)car-
bamoyl)cyclohexyl 3- ethylazetidine-1-car- boxylate 667.6 7.48
##STR01056## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)car- bamoyl)cyclohexyl 3-methoxyazetidine-
1-carboxylate 669.5 7.49 ##STR01057## trans-4-(((trans-4-(3-
Cyano-4-methoxy- phenyl)cyclohexyl)- methyl)(4-(1-iso-
propyl-1H-pyrazol-4- yl)pyridin-2-yl)car- bamoyl)cyclohexyl 3-
isopropoxyazetidine- 1-carboxylate 697.6 7.50 ##STR01058##
trans-4-(((trans-4-(3- Cyano-4-methoxy- phenyl)cyclohexyl)-
methyl)(4-(1-iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)car-
bamoyl)cyclohexyl 3-(dimethylamino)- azetidine-1-carbox- ylate
682.8 7.51 ##STR01059## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(1-iso- propyl-1H-pyrazol-
4-yl)pyridin-2-yl)car- bamoyl)cyclohexyl 3-(hydroxymethyl)-
azetidine-1-carbox- ylate 669.8 7.52 ##STR01060##
trans-4-((3-(1-Iso- propyl-1H-pyrazol-4- yl)phenyl)((trans-4-
(5-methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-methoxyazetidine- 1-carboxylate 658.5 7.53
##STR01061## trans-4-((3-(1-Iso- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (5-methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-(dimethylamino)-
azetidine-1-carbox- ylate 671.6 7.54 ##STR01062##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)meth-
yl)carbamoyl)cyclo- hexyl 3-ethylazeti- dine-1-carboxylate 657.5
7.55 ##STR01063## trans-4-((4-(1-Iso- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-methoxyazetidine-
1-carboxylate 659.5 7.56 ##STR01064## trans-4-((4-(1-Iso-
propyl-1H-pyrazol-4- yl)pyridin-2-yl)- ((trans-4-(5-methoxy-
6-methylpyridin-2- yl)cyclohexyl)meth- yl)carbamoyl)cyclo- hexyl
3-isopropoxy- azetidine-1-carbox- ylate 687.5 7.57 ##STR01065##
trans-4-((4-(1-Iso- propyl-1H-pyrazol-4- yl)pyridin-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-isopropylazetidine- 1-carboxylate 671.5
7.58.sup.3 ##STR01066## trans-4-((4-(1-Iso- propyl-1H-pyrazol-4-
yl)pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-(dimethylamino)-
azetidine-1-carbox- ylate 672.6 7.59 ##STR01067##
trans-4-((4-(1-Iso- propyl-1H-pyrazol- 4-yl)pyridin-2-yl)-
((trans-4-(5-methoxy- 6-methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-(hydroxymethyl)- azetidine-1-carbox- ylate
659.5 7.60 ##STR01068## trans-4-((3-(1-Iso- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (5-methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-ethylazetidine-1- carboxylate
656.3 7.61 ##STR01069## trans-4-((3-(1-Iso- propyl-1H-pyrazol-4-
yl)phenyl)((trans-4- (5-methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-(hydroxymethyl)-
azetidine-1-carbox- ylate 658.4 7.62.sup.1 ##STR01070##
trans-4-((3-(2-Cyclo- propyloxazol-4-yl)- phenyl)((trans-4-(4-
methoxy-3-methyl- phenyl)cyclohexyl)- methyl)carbamoyl)- cyclohexyl
3-hydroxy- azetidine-1-carbox- ylate 642.4 7.63 ##STR01071##
trans-4-((3-(2-Cyclo- propyloxazol-4-yl)- phenyl)((trans-4-(6-
(dimethylamino)- pyridine-3-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 642.5 7.64
##STR01072## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(4- methoxy-3-methyl- phenyl)cyclohexyl)-
methyl)carbamoyl)- cyclohexyl 3-hydroxy- azetidine-1-carbox- ylate
644.5 7.65 ##STR01073## trans-4-((3-(2-Iso- propyloxazol-4-yl)-
phenyl)((trans-4-(5- methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-hydroxyazetidine-
1-carboxylate 645.5 7.66 ##STR01074## trans-4-((3-(2-Cyclo-
propyloxazol-4-yl)- phenyl)((trans-4-(5- methoxy-6-methyl-
pyridin-2-yl)cyclo- hexyl)methyl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 643.3 7.67 ##STR01075##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(4-methoxy-3- methylphenyl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 643.5 7.68
##STR01076## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(3-(2-cyclo- propyloxazol-4-yl)-
phenyl)carbamoyl)- cyclohexyl 3-hydroxy- azetidine-1-carbox- ylate
653.8 7.69 ##STR01077## trans-4-(((trans-4-(3- Cyano-4-methoxy-
phenyl)cyclohexyl)- methyl)(4-(2-cyclo- propyloxazol-4-yl)-
pyridine-2-yl)car- bamoyl)cyclohexyl 3-hydroxyazetidine-
1-carboxylate 654.6 7.70 ##STR01078## trans-4-(((trans-4-(6-
Cyano-5-methoxy- pyridin-2-yl)cyclo- hexyl)methyl)(3-(2-
cyclopropyloxazol- 4-yl)phenyl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 654.2 7.71 ##STR01079##
trans-4-((4-(2-Iso- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl 3-hydroxy- azetidine-1-carbox- ylate 646.6
7.72 ##STR01080## trans-4-(((trans-4-(6- Cyano-5-methoxy-
pyridin-2-yl)cyclo- hexyl)methyl)(4-(2- cyclopropyloxazol-
4-yl)pyridine-2-yl)- carbamoyl)cyclohexyl 3-hydroxyazetidine-
1-carboxylate 655.7 7.73 ##STR01081## trans-4-(((trans-4-(3-
Cyano-4-methoxy- phenyl)cyclohexyl)- methyl)(4-(2-iso-
propyloxazol-4-yl)- pyridine-2-yl)car- bamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 656.5 7.74 ##STR01082##
trans-4-(((trans-4-(6- Cyano-5-methoxy- pyridin-2-yl)cyclo-
hexyl)methyl)(3-(2- isopropyloxazol-4-yl)- phenyl)carbamoyl)-
cyclohexyl 3-hydroxy- azetidine-1-carbox- ylate 656.6 7.75
##STR01083## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl azetidine-1-carbox- ylate
628.6 7.76 ##STR01084## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-methoxyazetidine-
1-carboxylate 658.5 7.77 ##STR01085## trans-4-((4-(2-Cyclo-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-(methoxymethyl)- azetidine-1-carbox- ylate) 672.6 7.78
##STR01086## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl dimethylcarbamate 616.4
7.79 ##STR01087## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-(dimethylamino)-
azetidine-1-carbox- ylate 671.5 7.80 ##STR01088##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-(hydroxymethyl)- azetidine-1-carbox- ylate
658.6 7.81 ##STR01089## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(4-methoxy-3- methylphenyl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-(dimethylamino)-
azetidine-1-carbox- ylate 670.5 7.82 ##STR01090##
trans-4-((4-(2-Iso- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-methoxyazetidine- 1-carboxylate 660.6 7.83
##STR01091## trans-4-((4-(2-Iso- propyloxazol-4-yl)-
pyridin-2-yl)((trans-4- (5-methoxy-6-methyl- pyridin-2-yl)cyclo-
hexyl)methyl)car- bamoyl)cyclohexyl 3-isopropoxyazeti-
dine-1-carboxylate 688.8 7.84 ##STR01092## trans-4-((4-(2-Iso-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-(dimethylamino)- azetidine-1-carbox- ylate 673.6 7.85.sup.2
##STR01093## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-(2-methoxy-2-
oxoethyl)azetidine-1- carboxylate 700.6 7.86.sup.5 ##STR01094##
2-(1-(((trans-4-((4-(2- Cyclopropyloxazol- 4-yl)pyridine-2-yl)
((trans-4-(5-methoxy- 6-methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl)oxy)carbonyl)- azetidin-3-yl)acetic acid
686.6 7.87 ##STR01095## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-ethoxyazetidine-1-
carboxylate 672.6 7.88 ##STR01096## trans-4-((4-(2-Cyclo-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-cyanoazetidine-1- carboxylate 653.6 7.89 ##STR01097##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-methylazetidine-1- carboxylate 642.5 7.90
##STR01098## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-ethylazetidine-1-
carboxylate 656.5 7.91 ##STR01099## trans-4-((4-(2-Cyclo-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-isopropoxyazetidine- 1-carboxylate 686.6 7.92 ##STR01100##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(6-methoxy-5- methylpyridin-3-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-(dimethylamino)- azetidine-1-carbox- ylate
671.6 7.93 ##STR01101## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(6-methoxy-5- methylpyridin-3-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-methoxyazetidine-
1-carboxylate 658.6 7.94 ##STR01102## trans-4-((4-(2-Cyclo-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(6-methoxy-5-
methylpyridin-3-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-hydroxyazetidine- 1-carboxylate 644.5 7.95 ##STR01103##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-(2-methoxyethoxy)- azetidine-1-carboxylate
702.6 7.96 ##STR01104## 4-((4-(2-Cyclopropyl- oxazol-4-yl)pyridine-
2-yl)((4-(5-methoxy- 6-methylpyridin-2- yl)cyclohexyl)methyl)-
carbamoyl)cyclo- hexyl-cis-3-hydroxy- azetidine-1-carbox- ylate
644.5 7.97 ##STR01105## trans-4-((4-(2-Iso- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-(hydroxymethyl)-
azetidine-1-carbox- ylate 660.4 7.98 ##STR01106##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-ethynylazetidine-1- carboxylate 652.6 7.99
##STR01107## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-(2-hydroxypropan-
2-yl)azetidine-1-car- boxylate 686.6 7.100 ##STR01108##
trans-4-((4-(2-Iso- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-ethylazetidine-1- carboxylate 658.5 7.101
##STR01109## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-((methylsulfonyl)-
methyl)azetidine-1- carboxylate 720.5 7.102 ##STR01110##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridine-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 3-isopropylazetidine- 1-carboxylate 670.5
7.103 ##STR01111## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridine-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-(tert-butyl)azetidine-
1-carboxylate 684.5 7.104 ##STR01112## trans-4-((4-(2-Cyclo-
propyloxazol-4-yl)- pyridine-2-yl)((trans- 4-(5-methoxy-6-
methylpyridin-2-yl)- cyclohexyl)methyl)- carbamoyl)cyclohexyl
3-propoxyazetidine- 1-carboxylate 686.5 7.105 ##STR01113##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridin-2-yl)((trans-4-
(5-methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-propylazetidine-1- carboxylate 670.7 7.106
##STR01114## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclohexyl 3-((dimethylamino)-
methyl)azetidine-1- carboxylate 685.5 7.107 ##STR01115##
trans-4-((4-(2-Cyclo- propyloxazol-4-yl)- pyridin-2-yl)((trans-
4-(5-methoxy-6- methylpyridin-2-yl)- cyclohexyl)methyl)-
carbamoyl)cyclohexyl 2-methylmorpholine- 4-carboxylate 672.8
7.108.sup.4 ##STR01116## trans-4-((4-(2-Cyclo- propyloxazol-4-yl)-
pyridin-2-yl)((trans- 4-(5-methoxy-6- methylpyridin-2-yl)-
cyclohexyl)methyl)- carbamoyl)cyclo- hexyl 3-hydroxy-[1,3'-
biazetidine]-1'-carbox- ylate 699.4 7.109 ##STR01117##
trans-4-((4-(2-Ethyl- oxazol-4-yl)pyridin- 2-yl)((trans-4-(5-
methoxy-6-methyl- pyridin-2-yl)cyclo- hexyl)methyl)car-
bamoyl)cyclohexyl 3-hydroxyazetidine- 1-carboxylate 632.3
Acyl-imidazole formation: .sup.1DMF as solvent. Carbamate
formation: Reactions that progressed slowly at rt were either
allowed to stir for multiple days or heated (50-80.degree. C.);
.sup.2Amine was a TFA salt; .sup.3Amine was a dihydrochloride salt;
.sup.4Amine was an oxalate salt. .sup.5From respective methyl ester
(1M NaOH, THF, MeOH, rt). .sup.6From respective Boc-protected amine
(20% TFA in CH.sub.2Cl.sub.2).
Compound 8
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfinyl)methyl)azetidine-1-carboxylate
##STR01118##
[0757] Sodium periodate (0.12 mL, 0.438 mmol, 3.5 M in H.sub.2O)
was added to a mixture of Compound 4.28 (200 mg, 0.292 mmol) in THF
(1 mL) at 0.degree. C. The mixture was stirred at rt overnight and
then diluted with EtOAc (10 mL). The organic layer was washed with
sat. aq. NaHCO.sub.3 (2.times.5 mL) and brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated, and purified by
reverse-phase prep-HPLC (water(0.04%NH.sub.4OH+10 mM
NH.sub.4HCO.sub.3)/CH.sub.3CN) to give
trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfinyl)methyl)azetidine-1-carboxylate (105 mg, 51%) as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.34 (s,
1H), 7.94 (s, 1H), 7.61 (d, 1H), 7.55 (s, 1H), 7.44 (t, 1H), 7.10
(d, 1H), 6.99-6.91 (m, 2H), 6.82-6.71 (m, 1H), 4.38-4.26 (m, 1H),
4.01-3.90 (m, 2H), 3.83-3.43 (m, 8H), 3.13-2.82 (m, 3H), 2.51 (s,
3H), 2.38-2.29 (t, 1H), 2.19-2.02 (m, 4H), 1.89-1.63 (m, 8H),
1.55-1.36 (m, 3H), 1.36-1.20 (m, 2H), 1.18-0.83 (m, 8H); LCMS:
701.5 [M+H].sup.+.
[0758] The Compound below was synthesized from Compound 6.30
following the procedure described for Compound 8.
TABLE-US-00030 Cmpd Structure Name [M + H].sup.+ 8.01.sup.1
##STR01119## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl 3-
(methylsulfinyl)azetidine-1-carboxylate 687.5 .sup.1NaIO.sub.4
(0.15M in CH.sub.3OH); CH.sub.3OH instead of THF as solvent.
Compound 9
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfonyl)methyl)azetidine-1-carboxylate
##STR01120##
[0760] meta-Chloroperoxybenzoic acid (118.5 mg, 0.584 mmol, 85%)
was added to a solution of Compound 4.28 (200.0 mg, 0.292 mmol) in
CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. The reaction was stirred
for 1 h at rt and then diluted with EtOAc (10 mL). The organic
layer was washed with sat. aq. NaHCO.sub.3 (2.times.5 mL), washed
with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered,
concentrated, and then purified by reverse-phase prep-HPLC
(water(0.04%NH.sub.4OH+10 mM NH.sub.4HCO.sub.3)/CH.sub.3CN) to give
trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3--
methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl
3-((methylsulfonyl)methyl)azetidine-1-carboxylate (80.1 mg, 38%) as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.35 (s,
1H), 7.95 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.45 (t, 1H), 7.11
(d, 1H), 6.99-6.92 (m, 2H), 6.84-6.73 (m, 1H), 4.40-4.26 (m, 1H),
4.01-3.90 (m, 2H), 3.80-3.49 (m, 8H), 3.45 (d, 2H), 3.07-2.96 (m,
1H), 2.92 (s, 3H), 2.39-2.28 (m, 1H), 2.19-2.04 (m, 4H), 1.89-1.65
(m, 8H), 1.57-1.38 (m, 3H), 1.38-1.22 (m, 2H), 1.14-0.82 (m, 8H);
LCMS: 717.5 [M+H].sup.+.
Compound 10
trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-trans-4-hydroxycyclohex-
anecarboxylate
##STR01121##
[0762] The title compound was isolated during the purification of
Intermediate 29.11. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.34 (s, 1H), 7.94 (s, 1H), 7.61 (d, 1H), 7.55 (s, 1H), 7.44 (t,
1H), 7.10 (d, 1H), 6.94 (s, 2H), 6.78 (d, 1H), 4.55-4.44 (m, 2H),
3.78-3.69 (m, 4H), 3.63-3.49 (m, 2H), 3.30-3.25 (m, 1H), 2.39-2.28
(m, 1H), 2.19-2.01 (m, 5H), 1.86-1.66 (m, 12H), 1.56-1.39 (m, 3H),
1.37-1.20 (m, 4H), 1.14-0.87 (m, 10H); LCMS: 668.5 [M+H].sup.+.
Compound 11
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy)cyclohexanecarboxami-
de
##STR01122##
[0763] Step 1:
trans-4-(Allyloxy)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-
-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
[0764] Sodium hydride (178.9 mg, 4.47 mmol, 60% purity) was added
to a solution of Intermediate 26 (500 mg, 0.894 mmol) in THF (25
mL) at 0.degree. C. The reaction was stirred at 0.degree. C. for 1
h under N.sub.2, and then 3-bromoprop-1-ene (649.5 mg, 5.37 mmol)
was added. The reaction was stirred at 70.degree. C. overnight, and
then more 3-bromoprop-1-ene (649.5 mg, 5.37 mmol) was added. The
reaction was stirred at 70.degree. C. overnight, water (30 mL) was
added, and the mixture was extracted with EtOAc (2.times.50 mL).
The organic layers were combined, washed with water (30 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated and then purified by
chromatography on silica gel (petroleum ether/EtOAc=20/1) to give
trans-4-(allyloxy)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-
-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(420 mg, 78%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.69 (s, 1H), 7.47-7.41 (m, 1H), 7.40-7.32 (m, 1H), 7.21
(t, 1H), 7.04 (d, 1H), 6.91-6.86 (m, 2H), 6.66 (d, 1H), 5.86-5.72
(m, 1H), 5.16(d, 1H), 5.05 (d, 1H), 3.88 (d, 2H), 3.72 (s, 3H),
3.55 (d, 2H), 3.25-3.13 (m, 1H), 2.36-2.22 (m, 2H), 2.14-2.01 (m,
4H), 1.98-1.89 (m, 2H), 1.85-1.63 (m, 6H), 1.61-1.44 (m, 3H),
1.39-1.26 (m, 2H), 1.16-1.01 (m, 6H), 0.96-0.84 (m, 2H); LCMS:
599.4 [M+H].sup.+.
Step 2:
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)-4-(2-oxoethoxy)cyclohexanecarboxamide
[0765] Potassium osmate(VI) dihydrate (153.8 mg, 0.417 mmol) and
18-crown-6 (441.3 mg, 1.67 mmol) were added to a solution of
trans-4-(allyloxy)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-
-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(500 mg, 0.834 mmol), NaIO.sub.4 (535.7 mg, 2.50 mmol), THF (16 mL)
and H.sub.2O (10 mL) at rt. The reaction was stirred at rt
overnight, poured into water (20 mL), and extracted with EtOAc
(2.times.50 mL). The combined organic layers were washed with water
(10 mL), washed with brine (10 mL), dried (Na.sub.2SO.sub.4),
filtered, concentrated and then purified by prep-TLC (petroleum
ether/EtOAc=1 /1) to give
trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-oxoethoxy)cyclohexanecarboxamide
(130 mg, 26%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 9.67 (s, 1H), 7.79 (s, 1H), 7.56-7.40 (m, 2H), 7.29-7.26
(m, 1H), 7.12 (d, 1H), 6.99-6.93 (m, 2H), 6.74 (d, 1H), 4.05 (s,
2H), 3.80 (s, 3H), 3.63 (d, 2H), 3.29 (t, 1H), 2.46-2.29 (m, 2H),
2.23-2.10 (m, 4H), 2.09-1.97 (m, 2H), 1.93-1.72 (m, 5H), 1.71-1.58
(m, 2H), 1.44-1.11 (m, 10H), 1.10-0.94 (m, 2H); LCMS: 601.4
[M+H].sup.+.
Step 3:
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-metho-
xy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy)cyclohexanec-
arboxamide hydrochloride
[0766] Acetic acid (10.9 mg, 0.183 mmol) was added to a solution of
trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-oxoethoxy)cyclohexanecarboxamide
(110 mg, 183.09 umol) and methanamine (2 M in THF, 1.83 mL, 3.66
mmol) in DCE (5 mL) at rt. The reaction was stirred at rt for 3 h.
Sodium triacetoxyborohydride (116.4 mg, 0.549 mmol) was added. The
reaction was stirred at rt overnight, poured into sat. aq.
NaHCO.sub.3 (20 mL), and extracted with CH.sub.2Cl.sub.2
(5.times.20 mL). The organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered, concentrated and then purified by
reverse-phase HPLC (water(0.05% HCl)/CH.sub.3CN) to give
trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy)cyclohexanecarboxam-
ide hydrochloride (25.6 mg, 21%) as a yellow solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.89-8.78 (m, 2H), 8.14 (s, 1H),
7.64-7.58 (m, 2H), 7.58-7.47 (m, 1H), 7.28 (d, 1H), 6.98-6.90 (m,
2H), 6.80-6.76 (m, 1H), 3.72 (s, 3H), 3.64-3.51 (m, 4H), 3.22 (t,
1H), 2.99-2.62 (m, 2H), 2.49-2.42 (m, 4H), 2.33 (t, 1H), 2.12-2.07
(m, 4H), 1.95 (d, 2H), 1.80-1.63 (m, 6H), 1.51-1.36 (m, 3H),
1.35-1.21 (m, 2H), 1.21-1.13 (m, 2H), 1.12-0.97 (m, 4H), 0.87-0.73
(m, 2H); LCMS: 616.4 [M+H].sup.+.
Compound 12
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)acetic
Acid
##STR01123##
[0767] Step 1:
tert-Butyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4--
(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)aceta-
te
[0768] tert-Butylammonium bromide (29.6 mg, 0.092 mmol) was added
to a mixture of Intermediate 29.12 (500 mg, 0.92 mmol), tert-butyl
2-bromoacetate (896.8 mg, 4.6 mmol), NaOH (4 mL, 50% in H.sub.2O)
and toluene (10 mL) at rt. The reaction was heated to 90.degree.
C., stirred overnight, poured into H.sub.2O (20 mL) and then
extracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined
organic layers were washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
chromatography on silica gel (petroleum ether/EtOAc=50/50) to give
tert-butyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4--
(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)aceta-
te (400 mg, 65%) as a yellow oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.32 (s, 1H), 7.94 (s, 1H), 7.64-7.58 (m,
1H), 7.55 (s, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.97-6.89 (m, 2H),
6.82-6.74 (m, 1H), 4.58-4.42 (m, 1H), 3.94-3.86 (m, 2H), 3.71 (s,
3H), 3.65-3.45 (m, 2H), 3.23-3.10 (m, 1H), 2.40-2.30 (m, 1H),
2.14-2.02 (m, 4H), 1.96-1.85 (m, 2H), 1.80-1.63 (m, 6H), 1.47-1.41
(m, 9H), 1.38 (s, 9H), 1.32-1.23 (m, 2H), 1.08-0.96 (m, 2H),
0.84-0.67 (m, 2H); LCMS: 658.5 [M+H].sup.+.
Step 2:
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)acetic
Acid
[0769] A mixture of
tert-butyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4--
(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)aceta-
te (400 mg, 0.61 mmol) and HCl in dioxane (4 M, 20 mL) was stirred
at rt for 1 h. The reaction mixture was concentrated and then
purified by reverse-phase HPLC (water(0.05% HCO-MeCN) to give a
white solid. The solid was dissolved in H.sub.2O (3 mL), adjusted
to pH=9 with NaOH (1 M), adjusted to pH=6 with HCl (1 M) at rt,
stirred at rt for 10 min, filtered, and then dried under vacuum to
give
2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methypcarbamoyl)cyclohexyl)oxy)acetic
acid (200 mg, 55%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.44-12.25 (m, 1H), 8.32 (s, 1H), 7.94 (s,
1H), 7.61 (d, 1H), 7.55 (s, 1H), 7.44 (t, 1H), 7.09 (d, 1H),
7.00-6.91 (m, 2H), 6.84-6.74 (m, 1H), 4.58-4.42 (m, 1H), 3.88 (s,
2H), 3.71 (s, 3H), 3.65-3.42 (m, 2H), 3.25-3.13 (m, 1H), 2.40-2.24
(m, 1H), 2.17-2.05 (m, 4H), 1.97-1.85 (m, 2H), 1.81-1.60 (m, 6H),
1.48-1.24 (m, 11H), 1.13-0.96 (m, 2H), 0.85-0.66 (m, 2H); LCMS:
602.4 [M+H].sup.+.
Compound 13
trans-4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-metho-
xythiazol-5-yl)phenyl)carbamoyl)cyclohexyl dimethylcarbamate
##STR01124##
[0771] Intermediate 22 (200 mg, 0.364 mmol) was dissolved in THF
(5.0 mL) at 0.degree. C. Sodium hydride (60% purity, 43.7 mg, 1.09
mmol) was added at 0.degree. C. The solution was stirred at
0.degree. C. for 0.5 h. Dimethylcarbamic chloride (47.0 mg, 0.437
mmol) in THF (5.0 mL) was added slowly. The solution was stirred at
60.degree. C. overnight, quenched with sat'd NH.sub.4Cl (10 mL),
and then extracted with EtOAc (3.times.15 mL). The organics were
washed with brine (2.times.15 mL), concentrated, and purified first
by RP-HPLC [water (10 mM NH.sub.4HCO.sub.3)--MeCN] and then
prep-TLC (petroleum ether:EtOAc=1:1) to give
trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-meth-
oxythiazol-5-yl)phenyl)carbamoyl)cyclohexyl dimethylcarbamate (31.1
mg) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
7.74 (s, 1H), 7.44-7.54 (m, 3H), 7.23 (d, 1H), 6.91-6.93 (m, 2H),
6.76 (d, 1H), 4.32-4.33 (m, 1H), 4.04 (s, 3H), 3.69 (s, 3H), 3.54
(s, 2H), 2.71 (s, 6H), 2.30-2.31 (m, 1H), 2.06-2.08 (m, 4H),
1.82-1.83 (m, 2H), 1.71-1.73 (m, 6H), 1.40-1.53 (m, 3H), 1.20-1.32
(m, 2H), 0.90-1.08 (m, 4H); LCMS: 531.3
[M-OC(O)N(CH.sub.3).sub.2].sup.+.
[0772] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate alkyl halide following the
procedure described for Compound 13.
TABLE-US-00031 Cmpd Structure Name [M + H].sup.+ 13.01 ##STR01125##
trans-N-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- methoxyethoxy)-N-(3-(2-
methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide 607.3 13.02
##STR01126## trans-N-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- methoxypropoxy)-N-(3-(2-
methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide 621.3
13.03.sup.2,3 ##STR01127## trans-4-(2-Hydroxyethoxy)-N-((trans-4-
(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-N-(3-
(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide 593.4
13.04.sup.4 ##STR01128## trans-4-(3-Hydroxypropoxy)-N-((trans-
4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-N-(3-
(2-methoxythiazol-5- yl)phenyl)cyclohexanecarboxamide 607.3
13.05.sup.1 ##STR01129## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-(dimethylamino)ethoxy)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)cyclo- hexanecarboxamide 630.5
.sup.1Heated at 65.degree. C.; .sup.2Heated at 70.degree. C.;
.sup.3From THP-protected bromo-alcohol, the deprotection
(p-TsOH.cndot.H.sub.2O, CH.sub.2Cl.sub.2, CH.sub.3OH, rt, 3 h);
.sup.42-(3-bromopropoxy)tetrahydro-2H-pyran, nBu.sub.4NBr, KOH,
toluene, rt, overnight; then additional KOH, rt, overnight; then
deprotection (p-TsOH.cndot.H.sub.2O, CH.sub.2Cl.sub.2, CH.sub.3OH,
rt, 3 h).
Compound 14
Ethyl
2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-me-
thoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate
##STR01130##
[0774] Intermediate 14.28 (50 mg, 0.12 mmol) and
trans-4-(2-ethoxy-2-oxoethyl)cyclohexancarboxylic acid (40 mg, 0.19
mmol) were dissolved in CH.sub.2Cl.sub.2 (1 mL). Pyridine (40 0.49
mmol) followed by 1-propylphosphonic acid cyclic anhydride (50 wt.
% in CH.sub.2Cl.sub.2; 90 0.19 mmol) were added to the reaction at
rt. The reaction was stirred at rt overnight and then heated at
40.degree. C. for 3.5 h. Additional 1-propylphosphonic acid cyclic
anhydride (50 wt. % in CH.sub.2Cl.sub.2; 3 .mu.L, 0.006 mmol) was
added. The reaction was heated at 40.degree. C. for .about.7 h and
then diluted with EtOAc (20 mL). The organics were washed with
water (20 mL), washed with saturated NaHCO.sub.3 (20 mL), washed
with brine (20 mL), dried (Na.sub.2SO.sub.4), filtered,
concentrated and then purified by silica gel chromatography (20-70%
EtOAc in hexanes) to give ethyl
2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-
-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate
as an off-white foam (47 mg, 64% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.93 (s, 1H), 7.59 (d, 1H),
7.53 (s, 1H), 7.43 (t, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.98 (d,
1H), 3.99 (q, 2H), 3.79-3.70 (m, 4H), 3.67-3.46 (m, 2H), 2.29 (s,
3H), 2.13-2.01 (m, 3H), 1.82-1.72 (m, 4H), 1.70-1.51 (m, 5H),
1.48-1.30 (m, 5H), 1.17-0.95 (m, 10H), 0.70-0.56 (m, 2H); LCMS:
613.6 [M+H].sup.+.
Compound 15
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(hydroxymethyl)-N-((tr-
ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
##STR01131##
[0776] Sodium borohydride (35 mg, 0.92 mmol) was added to a mixture
of Compound 18.13 (50 mg, 0.086 mmol), LiCl (9 mg, 0.21 mmol), and
THF (2 mL). The mixture was stirred at rt for 25 min, heated at
80.degree. C. for 2 h, allowed to cool to rt, and then diluted with
EtOAc (20 mL). The organic layer was washed (2.times.20 mL
saturated NaHCO.sub.3 and then 20 mL brine), dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by silica gel chromatography (0-5% CH.sub.3OH in
CH.sub.2Cl.sub.2) to give
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(hydroxymethyl)-N-((t-
rans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(41 mg, 86%) as a white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.34 (s, 1H), 7.93 (s, 1H), 7.58 (d, 1H), 7.55-7.51 (m,
1H), 7.43 (t, 1H), 7.08 (d, 1H), 6.97-6.92 (m, 2H), 6.80-6.75 (m,
1H), 4.26 (t, 1H), 3.77-3.72 (m, 1H), 3.71 (s, 3H), 3.65-3.41 (m,
2H), 3.07 (t, 2H), 2.38-2.27 (m, 1H), 2.08 (s, 3H), 2.07-2.02 (m,
1H), 1.80-1.57 (m, 8H), 1.47-1.18 (m, 6H), 1.11-0.95 (m, 6H),
0.62-0.46 (m, 2H); LCMS: 556.4 [M+H].sup.+.
[0777] The Compounds below were synthesized from the appropriate
methyl ester following the procedure described for Compound 15.
TABLE-US-00032 Cmpd Structure Name [M + H].sup.+ 15.01.sup.1
##STR01132## trans-4-(Hydroxymethyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)- N-(3-(2-methoxythiazol-5-
yl)phenyl)cyclohexanecarboxamide 563.5 15.02.sup.2 ##STR01133##
trans-N-(3-(2-Cyclopropylthiazol- 5-yl)phenyl)-4-(hydroxymethyl)-N-
((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
cyclohexanecarboxamide 573.5 15.03.sup.2 ##STR01134##
trans-4-(Hydroxymethyl)-N-(4-(1- isopropyl-1H-pyrazol-4-yl)pyridin-
2-yl)-N-((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexane- carboxamide 560.3 15.04.sup.3
##STR01135## trans-N-(4-(2-Cyclopropyloxazol- 4-yl)pyridin-2-yl)-4-
(hydroxymethyl)-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)cyclohexane- carboxamide 587.6 .sup.1Heated at
60.degree. C. for 1 h, 70.degree. C. for 4 h, and then 80.degree.
C. for 1 h; .sup.2Heated at 80.degree. C. overnight; .sup.3Heated
at 80.degree. C. for 5 h, additional NaBH.sub.4 added, and then
heated at 80.degree. C. for 1 h.
Compound 16
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)-
pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
Acid
##STR01136##
[0779] Aqueous sodium hydroxide (1 N, 0.3 mL, 0.3 mmol) was added
to a solution of Compound 18.08 (37 mg, 0.061 mmol), THF (0.6 mL)
and CH.sub.3OH (0.3 mL) at rt. The mixture was stirred for 4.5 h
and then poured into a mixture of 20 mL sat'd NH.sub.4Cl and 0.3 mL
1 N HCl. This mixture was extracted with EtOAc. Additional 1 N HCl
(0.2 mL) was added to the aqueous layer to bring pH from 5 to 3.
The aqueous layer was extracted with original EtOAc, and then the
EtOAc layer was washed with 20 mL brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated. The compound was observed in both
aqueous and organic layers. The aqueous layer was basified with 1 N
NaOH until pH-6, added to the concentrated residue, and then
extracted with EtOAc (2.times.20 mL). The combined extracts were
dried (Na.sub.2SO.sub.4), filtered, and concentrated to give
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethyl-
amino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic
acid (33 mg, 94%) as an off-white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.00 (br s, 1H), 8.09 (s, 1H), 7.88-7.82
(m, 1H), 7.62-7.55 (m, 2H), 7.55-7.48 (m, 2H), 7.30-7.24 (m, 1H),
6.75-6.67 (m, 1H), 3.63-3.53 (m, 2H), 3.02 (s, 6H), 2.47-2.41 (m,
1H), 2.41-2.31 (m, 1H), 2.17-2.04 (m, 2H), 1.86-1.65 (m, 8H),
1.51-1.36 (m, 3H), 1.36-1.26 (m, 2H), 1.18-1.11 (m, 2H), 1.11-0.87
(m, 6H); LCMS: 587.4 [M+H].sup.+.
Compound 17
trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methy-
lphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic Acid
##STR01137##
[0781] Aqueous sodium hydroxide (1 N, 1.25 mL, 1.25 mmol) was added
to a solution of Compound 18.06 (153 mg, 0.25 mmol), CH.sub.3OH
(1.25 mL) and THF (2.50 mL) at rt. The reaction was stirred for 2
h, concentrated, diluted with 2 mL water and then acidified at
0.degree. C. with 1.3 mL 1 N HCl. The mixture was diluted with
EtOAc. The organics were washed with 30 mL brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and dried on high
vacuum overnight to give
trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid
(142 mg, 95%) as an off-white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.99 (s, 1H), 8.10 (s, 1H), 7.63-7.56 (m,
2H), 7.52 (t, 1H), 7.31-7.24 (m, 1H), 6.98-6.91 (m, 2H), 6.82-6.74
(m, 1H), 3.72 (s, 3H), 3.62-3.49 (m, 2H), 2.4-2.39 (m, 1H),
2.39-2.28 (m, 1H), 2.17-2.03 (m, 5H), 1.86-1.64 (m, 8H), 1.50-1.36
(m, 3H), 1.36-1.24 (m, 2H), 1.18-1.11 (m, 2H), 1.11-0.87 (m, 6H);
LCMS: 587.4 [M+H].sup.+.
[0782] The Compounds below were synthesized from the appropriate
ester Intermediates following the procedure described for Compounds
16 and 17.
TABLE-US-00033 Cmpd Structure Name [M + H].sup.+ 17.01.sup.4
##STR01138## trans-4-(((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-
yl)phenyl)carbamoyl)cyclohexanecar- boxylic acid 577.3 17.02.sup.4
##STR01139## 4-(((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-
yl)phenyl)carbamoyl)bicyclo[2.2.2]oc- tane-1-carboxylic acid 603.5
17.03.sup.4 ##STR01140## trans-4-(((trans-4-(3-Chloro-4-
methoxyphenyl)cyclohexyl)methyl)(3- (2-cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexanecar- boxylic acid 607.3 17.04
##STR01141## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(3-fluoro-1- methyl-1H-indazol-5-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylic acid 615.4
17.05.sup.4 ##STR01142## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecar- boxylic acid 613.4 17.06
##STR01143## trans-4-((3-(2-Cyclopropylthiazol-5- yl)phenyl)((4-(6-
(dimethylamino)pyridin-3- yl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecar- boxylic acid 613.4
17.07.sup.1,5 ##STR01144## trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecar- boxylic acid 614.4
TABLE-US-00034 Cmpd Structure Name [M + H].sup.+ 17.08.sup.1
##STR01145## trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylic acid 588.4
17.09.sup.1 ##STR01146## trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(4-methoxy- 3-
methylphenyl)cyclohexyl)methyl)car- bamoyl)cyclohexanecarboxylic
acid 588.5 17.10.sup.1 ##STR01147##
trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(5-methoxy- 6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylic acid 589.4
17.11.sup.2 ##STR01148## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (2-cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexanecar- boxylic acid 598.3 17.12.sup.2
##STR01149## trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)(3-(2- cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexanecar- boxylic acid 599.6 17.13.sup.6
##STR01150## trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)car- bamoyl)cyclohexanecarboxylic
acid 570.4 17.14.sup.3 ##STR01151## trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(6- (dimethylamino)pyridin-3-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylic acid 570.5
17.15.sup.4 ##STR01152## trans-4-(((trans-4-(3-Chloro-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexanecar- boxylic acid 590.3
TABLE-US-00035 Cmpd Structure Name [M + H].sup.+ 17.16 ##STR01153##
trans-4-((3-(1-Cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(3-
fluoro-1-methyl-1H-indazol-5- yl)cyclohexyl)methyl)carbamoyl)cyclo-
hexanecarboxylic acid 598.3 17.17.sup.4 ##STR01154##
trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecar- boxylic acid 596.4 17.18
##STR01155## trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylic acid 571.5
17.19.sup.2 ##STR01156## trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((4-(4- methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecar- boxylic acid 597.5 17.20
##STR01157## trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)car- bamoyl)cyclohexanecarboxylic
acid 571.5 17.21.sup.3,6 ##STR01158##
trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylic acid 572.5
17.22.sup.2 ##STR01159## trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexanecar- boxylic acid 581.5 17.23.sup.4
##STR01160## 2-(trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 586.4
TABLE-US-00036 Cmpd Structure Name [M + H].sup.+ 17.24.sup.4
##STR01161## 2-(trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 585.5
17.25.sup.6 ##STR01162## 2-(trans-4-((4-(1-Isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 588.5
17.26.sup.3 ##STR01163## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin-
2-yl)carbamoyl)cyclohexyl)acetic acid 598.5 17.27.sup.3
##STR01164## 2-(trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)(4-(1-isopropyl- 1H-pyrazol-4-yl)pyridin-2-
yl)carbamoyl)cyclohexyl)acetic acid 599.5 Alternate conditions:
.sup.1THF/CH.sub.3OH (1:1); .sup.2LiOH.cndot.H.sub.2O, THF,
0.degree. C.-rt, 2 h. Isolation variations: .sup.3Acidified to pH =
6 before extraction; .sup.4Purifed by silica gel chromatography;
.sup.5Purified by reverse-phase HPLC; .sup.6Isolated as a solid by
filtration of aqueous after pH adjustment.
Compound 18
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclop-
ropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid
##STR01165##
[0783] Step 1:
5-(trans-4-(((3-(2-Cyclopropyloxazol-4-yl)phenyl)amino)methyl)cyclohexyl)-
-2-methoxybenzonitrile
[0784] Sodium triacetoxyborohydride (436 mg, 2.06 mmol) was added
to a solution of Intermediate 3.05 (200 mg, 0.82 mmol),
Intermediate 8.01 (165 mg, 0.82 mmol), and DCE (20 mL) at 0.degree.
C. under N.sub.2. The reaction was stirred at rt overnight, poured
into saturated NaHCO.sub.3 (30 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL). The combined organic layers were
washed (30 mL brine), dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The residue was purified by silica gel chromatography
(petroleum ether/EtOAc=17/3) to give
5-(trans-4-(((3-(2-cyclopropyloxazol-4-yl)phenyl)amino)methyl)cyclohexyl)-
-2-methoxybenzonitrile (250 mg, 66%) as a yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 7.71(s, 1H), 7.42-7.35 (m, 2H),
7.20-7.18 (m, 1H), 7.01-6.97 (m, 2H), 6.90 (d, 1H), 6.56 (d, 1H),
3.90 (s, 3H), 3.07 (d, 2H), 2.50-2.43 (m, 1H), 2.15-2.11 (m, 1H),
2.05-2.00 (m, 2H), 1.99-1.90 (m, 2H), 1.70-1.67 (m, 1H), 1.43-1.39
(m, 2H), 1.13-1.11 (m, 2H), 1.10-1.06 (m, 2H), 1.06-1.04 (m, 2H);
LCMS: 428.3 [M+H].sup.+.
Step 2:
trans-Methyl-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)meth-
yl)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylate
[0785] Intermediate 19.04 (20 mL in toluene, 1.87 mmol) was added
to a solution of
5-(trans-4-(((3-(2-cyclopropyloxazol-4-yl)phenyl)amino)methyl)cyclohexyl)-
-2-methoxybenzonitrile (200 mg, 0.47 mmol), pyridine (0.76 mL, 9.36
mmol), and dry CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. under
N.sub.2. The reaction was allowed to warm to rt, stirred overnight,
poured into saturated NaHCO.sub.3 (30 mL) and then extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL). The combined organic layers were
washed with brine (30 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The residue was purified by silica gel chromatography
(petroleum ether/EtOAc=4/1) to give
trans-methyl-4-0(trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)-
(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylate
(190 mg, 52%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.80 (s, 1H), 7.67 (d, 1H), 7.56 (s, 1H), 7.47-7.42 (m,
1H), 7.35-7.32 (m, 2H), 7.08 (d, 1H), 6.88 (d, 1H), 3.89 (s, 3H),
3.60 (s, 3H), 2.48-2.40 (m, 1H), 2.30-2.23 (m, 1H), 2.20-2.09 (m,
2H), 1.93-1.76 (m, 7H), 1.66-1.56 (m, 5H), 1.48-1.43 (m, 1H),
1.33-1.30 (m, 2H), 1.22-1.11 (m, 6H), 1.11-1.04 (m, 2H); LCMS:
596.4 [M+H].sup.+.
Step 3:
trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(-
2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic
acid
[0786] Lithium hydroxide monohydrate (169 mg, 4.03 mmol) was added
to a solution of
trans-methyl-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(-
2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylate
(300 mg, 0.5 mmol), THF (20 mL), and H.sub.2O (5 mL) at 0.degree.
C. The mixture was allowed to warm to rt and stirred overnight. THF
was removed under reduced pressure, and the mixture was diluted
with H.sub.2O (20 mL). The mixture was concentrated to remove water
(5 mL), and then hydrochloric acid (1 M) was added to the solution
at 0.degree. C. (pH=6). The resulting solid was collected by
filtration, washed with ice H.sub.2O (20 mL), and dried under
vacuum. The solid was purified by reverse-phase HPLC (water(0.05%
HCl)/CH.sub.3CN) to give
trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclo-
propyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid (130
mg, 44%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 11.95 (s, 1H), 8.52 (s, 1H), 7.75 (d, 1H), 7.65 (s, 1H),
7.53-7.49 (m, 3H), 7.24 (d, 1H), 7.12 (d, 1H), 3.86 (s, 3H), 3.56
(d, 2H), 2.45-2.42 (m, 1H), 2.19-2.13 (m, 1H), 2.10-2.07 (m, 2H),
1.81-1.72 (m, 6H), 1.69-1.66 (m, 2H), 1.46-1.31 (m, 5H), 1.07-1.04
(m, 4H), 1.00-0.99 (m, 2H), 0.98-0.88 (m, 2H); LCMS: 582.4
[M+H].sup.+.
[0787] The following Compounds were synthesized from the
appropriate Intermediates following the procedures described for
Compound 18.
TABLE-US-00037 Cmpd Structure Name [M + H].sup.+ 18.01.sup.1,2
##STR01166## trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclohexane- carboxylic acid 572.5
18.02.sup.1 ##STR01167## trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridine-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic
acid 572.5 18.03.sup.3 ##STR01168##
trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexanecarboxylic acid 598.5 18.04
##STR01169## trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(6- (dimethylamino)pyridine-3-
yl)cyclohexyl)methyl)carbamoyl)cyclohexane- carboxylic acid 571.4
18.05 ##STR01170## trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)(3-(2- cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 583.4 Alternate
condition: Step 2: .sup.1Base was Et.sub.3N. Isolation variations:
.sup.2Purifed by silica gel chromatography; .sup.3Filtered off
solids with H.sub.2O rinsing (no further purification).
[0788] The following Compounds were synthesized from the
appropriate Intermediates following the procedures described for
Compound 18, Steps 1 & 2.
TABLE-US-00038 Cmpd Structure Name [M + H].sup.+ 18.06.sup.2
##STR01171## trans-Methyl 4-((3-(2-
cyclopropylthiazol-5-yl)phenyl)((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexanecarboxylate
601.4 18.07 ##STR01172## trans-Methyl 4-(((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-
yl)phenyl)carbamoyl)cyclohexanecarbox- ylate 591.4 18.08
##STR01173## trans-Methyl 4-((3-(2-
cyclopropylthiazol-5-yl)phenyl)((trans-
4-(6-(dimethylamino)pyridin-3-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylate 601.4 18.09
##STR01174## trans-Methyl 4-(((trans-4-(6-cyano-5-
methoxypyridin-2- yl)cyclohexyl)methyl)(3-(2- cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexanecarbox- ylate 613.5 18.10.sup.2,5
##STR01175## Methyl 4-(((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)(3-(2- methoxythiazol-5-
yl)phenyl)carbamoyl)bicyclo[2.2.2]octane- 1-carboxylate 617.4 18.11
##STR01176## trans-4-(Benzyloxy)-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)-N- (3-(2-methoxythiazol-5-
yl)phenyl)cyclohexanecarboxamide 639.5 18.12 ##STR01177##
trans-N-((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)-4-
((4-methoxybenzyl)oxy)-N-(3-(2- methoxythiazol-5-
yl)phenyl)cyclohexanecarboxamide 669.4 18.13.sup.2 ##STR01178##
trans-methyl 4-((3-(1-cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexanecarboxylate
584.5 18.14.sup.2 ##STR01179## trans-Methyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(6-
(dimethylamino)pyridin-3- yl)cyclohexyl)methyl)carbamoyl)cyclo-
hexanecarboxylate 584.6 18.15 ##STR01180## tert-Butyl
(4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexyl)trans- carbamate 667.4 18.16
##STR01181## tert-Butyl (trans-4-((3-(1-isopropyl-
1H-pyrazol-4-yl)phenyl)((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)carbamate
665.5 M + Na 18.17.sup.3 ##STR01182## trans-Methyl
4-((4-(1-cyclopropyl-1H- pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-
methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclo-
hexanecarboxylate 586.6 18.18.sup.3 ##STR01183## Ethyl
2-(trans-4-((4-(1-cyclopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-
(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclo-
hexyl)acetate 614.6 18.19.sup.2 ##STR01184## trans-Methyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(5-
methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclo-
hexanecarboxylate 585.5 18.20.sup.4 ##STR01185## Ethyl
2-(trans-4-((4-(1-isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetate 616.5
18.21.sup.3 ##STR01186## Ethyl 2-(trans-4-(((trans-4-(3-cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(1-isopropyl-1H-pyrazol-4-yl)pyridin-
2-yl)carbamoyl)cyclohexyl)acetate 626.5 18.22.sup.3 ##STR01187##
Ethyl 2-(trans-4-(((trans-4-(6-cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)(4-(1-isopropyl- 1H-pyrazol-4-yl)pyridin-2-
yl)carbamoyl)cyclohexyl)acetate 627.5 18.23.sup.1,4 ##STR01188##
trans-Methyl 4-((4-(2- cyclopropyloxazol-4-yl)pyridin-2-
yl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexanecarboxylate 587.7 18.24
##STR01189## trans-Methyl 4-(((trans-4-(6-cyano-5-
methoxypyridin-2- yl)cyclohexyl)methyl)(3-(2- cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexanecarbox- ylate 597.4
[0789] Alternate conditions: Step 1: .sup.1Solvent was
CH.sub.2Cl.sub.2; Step 2: .sup.2Solvent was toluene; .sup.3DMAP,
pyridine 80.degree. C.; .sup.4DMAP, Et.sub.3N, toluene, 80.degree.
C., 2 h; .sup.550.degree. C., overnight.
Compound 19
2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic Acid
##STR01190##
[0790] Step 1: Methyl
2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate
[0791] A mixture of Intermediate 21.22 (450 mg, 0.773 mmol) and HCl
in CH.sub.3OH (4 M, 100 mL, 0.4 mol) was stirred at rt overnight,
and then heated to 65.degree. C. for 10 h. The mixture was allowed
to cool to rt, concentrated under reduced pressure, and then
diluted with EtOAc (50 mL). The organic layer was washed with aq.
sat. NaHCO.sub.3 (20 mL), washed with brine (20 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated and then purified by
chromatography on silica gel (petroleum ether/EtOAc=5/1) to give
methyl
2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate (270.2
mg, 57%) as a yellow solid. .sup.1H NMR (400 MHz,CDCl.sub.3):
.delta. 7.77 (s, 1H), 7.55-7.49 (m, 1H), 7.49-7.41 (m, 1H), 7.29
(t, 1H), 7.11 (d, 1H), 7.01-6.91 (m, 2H), 6.74 (d, 1H), 3.80 (s,
3H), 3.68-3.55 (m, 5H), 2.45-2.29 (m, 2H), 2.20 (s, 3H), 2.15-2.06
(m, 3H), 1.94-1.62 (m, 11H), 1.45-1.25 (m, 3H), 1.22-1.08 (m, 6H),
0.82-0.68 (m, 2H); LCMS: 615.4 [M+H].sup.+.
Step 2:
2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic
acid
[0792] Lithium hydroxide monohydrate (273 mg, 6.51 mmol) was added
to a solution of methyl
2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate (200.2
mg, 0.325 mmol), THF (6 mL) and H.sub.2O (6 mL) at rt. The mixture
was stirred at rt overnight. The organic solvent was removed under
reduced pressure, and the aqueous layer was extracted with EtOAc
(10 mL). The aqueous layer was adjusted to pH=1 with 3 M HCl and
then filtered. The cake was dried by vacuum to give
2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-m-
ethylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid
(166.9 mg, 85%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.96 (s, 1H), 8.07 (s, 1H), 7.63-7.44 (m,
3H), 7.25 (d, 1H), 7.03-6.90 (m, 2H), 6.80-6.65 (m, 1H), 3.71 (s,
3H), 3.59-3.54 (m, 2H), 2.46-2.39 (m, 1H), 2.39-2.27 (m, 1H),
2.14-2.01 (m, 4H), 1.95 (d, 2H), 1.79-1.71 (m, 4H), 1.68-1.58 (m,
4H), 1.56-1.53 (m, 1H), 1.46-1.33 (m, 3H), 1.31-1.21 (m, 2H),
1.18-0.93 (m, 6H), 0.71-0.52 (m, 2H); LCMS: 601.3 [M+H].sup.+.
Compound 20
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyc-
lopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic acid
##STR01191##
[0793] Step 1: tert-Butyl
2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cy-
clopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetate
[0794] Pyridine (1.25 g, 15.78 mmol) was added to a solution of
Intermediate 14.10 (200 mg, 0.451 mmol) in CH.sub.2Cl.sub.2 (5 mL)
under N.sub.2 at 0.degree. C., and then Intermediate 19.06 (7.7 mL
toluene solution, 3.83 mmol) was added. The reaction mixture was
warmed to rt, stirred overnight, poured into sat. aq. NaHCO.sub.3
(20 mL), and then extracted with EtOAc (3.times.20 mL). The
combined organic layers were washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
silica gel chromatography (petroleum ether/EtOAc=20/1.fwdarw.5/1)
to give tert-butyl
2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cy-
clopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetate (150 mg,
47%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.77 (s, 1H), 7.51 (d, 1H), 7.45 (t, 1H), 7.37-7.34 (m, 1H),
7.32-2.30 (m, 1H), 7.28-7.27 (m, 1H), 7.10 (d, 1H), 6.88 (d, 1H),
3.90 (s, 3H), 3.63 (d, 2H), 2.49-2.38 (m, 1H), 2.37-2.30 (m, 1H),
2.17-2.07 (m, 1H), 1.98 (d, 2H), 1.90-1.80 (m, 4H), 1.75-1.69 (m,
5H), 1.66-1.55 (m, 4H), 1.41 (s, 9H), 1.35-1.26 (m, 2H), 1.21-1.12
(m, 5H), 0.80-0.66 (m, 2H); LCMS: 668.4 [M+H].sup.+.
Step 2:
2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(-
3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic
acid
[0795] A mixture of tert-butyl
2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cy-
clopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetate (150 mg,
0.224 mmol) and HCl in dioxane (4 M, 50 mL) was stirred at rt for 1
h, concentrated to dryness, and then purified by reverse-phase HPLC
(water(10 mM HCl)/CH.sub.3CN) to give
2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cy-
clopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic acid (60
mg, 43%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 12.13 (s, 1H), 8.09 (s, 1H), 7.63-7.46 (m, 5H), 7.26 (d,
1H), 7.13 (d, 1H), 3.87 (s, 3H), 3.65-3.50 (m, 3H), 2.47-2.38 (m,
2H), 2.13-2.02 (m, 1H), 1.97 (d, 2H), 1.82-1.71 (m, 4H), 1.70-1.58
(m, 4H), 1.50-1.27 (m, 5H), 1.19-0.96 (m, 6H), 0.73-0.55 (m, 2H);
LCMS: 612.3 [M+H].sup.+.
[0796] The Compounds below were synthesized from the appropriate
Intermediates following the procedures described for Compound
20.
TABLE-US-00039 Cmpd Structure Name [M + H].sup.+ 20.01 ##STR01192##
2-(trans-4-(((trans-4-(6-Cyano-5- methoxypyridin-2-
yl)cyclohexyl)methyl)(3-(2- cyclopropylthiazol-5-
yl)phenyl)carbamoyl)cyclohexyl)acetic acid 613.5 20.02.sup.2
##STR01193## 2-(trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)acetic acid
602.3 20.03.sup.3 ##STR01194##
2-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 602.4
20.04.sup.1 ##STR01195## 2-(trans-4-((4-(2-Cyclopropylthiazol-5-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 603.5 20.05
##STR01196## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-
(2-cyclopropylthiazol-5-yl)pyridin-2-
yl)carbamoyl)cyclohexyl)acetic acid 613.3 20.06.sup.5 ##STR01197##
2-(trans-4-((3-(2-Cyclopropylthiazol-5- yl)phenyl)((trans-4-(6-
(dimethylamino)pyridin-3- yl)cyclohexyl)methyl)carbamoyl)cyclo-
hexyl)acetic acid 601.4 20.07 ##STR01198##
2-(trans-4-((3-(2-Isopropylthiazol-5-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 604.5
20.08.sup.1 ##STR01199## trans-2-(4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((4-(4- methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexyl)acetic acid 611.5 20.09.sup.4
##STR01200## 2-(trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)acetic acid
584.6 20.10.sup.2 ##STR01201## 2-(trans-4-((4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)acetic acid
585.5 20.11 ##STR01202## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3- (1-cyclopropyl-1H-pyrazol-4-
yl)phenyl)carbamoyl)cyclohexyl)acetic acid 595.6 20.12.sup.5
##STR01203## 2-(trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(6- (dimethylamino)pyridin-3-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 584.6 20.13
##STR01204## 2-(trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclo- hexyl)acetic acid 587.5 20.14
##STR01205## 2-(trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)acetic acid
586.6 20.15 ##STR01206## 2-(trans-4-((4-(1-Isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy- 3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)acetic acid
587.5 20.16 ##STR01207## 3-(trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carba- moyl)cyclohexyl)propanoic
acid 600.4 Alternate conditions: Step 1: .sup.1Base was Et.sub.3N;
.sup.2Pyridine, DMAP, 50-80.degree. C.; .sup.3Amine in pyridine
only (no CH.sub.2Cl.sub.2); Step 2: .sup.4HCl in EtOAc (4M);
.sup.5TFA in CH.sub.2Cl.sub.2.
Compound 21
trans-2-(4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-met-
hylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)acetic
Acid
##STR01208##
[0797] Step 1:
4-(2-Cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.-
2]octan-1-yl)methyl)pyridin-2-amine
[0798] Sodium triacetoxyborohydride (658 mg, 3.11 mmol) was slowly
added to a solution of Intermediate 10 (312 mg, 1.55 mmol),
Intermediate 5 (401 mg, 1.55 mmol), and DCE (5 mL) at 0.degree. C.
The mixture was allowed to warm to rt, stirred for 5 h, poured into
water (30 mL), and then extracted with EtOAc (3.times.20 mL). The
combined organic layers were washed with (2.times.20 mL brine),
dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue
was purified by silica gel chromatography (petroleum
ether/EtOAc=10/1.fwdarw.5/1) to give
4-(2-cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.-
2]octan-1-yl)methyl)pyridin-2-amine (254 mg, 35%) as a yellow oil.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.05 (d, 1H), 7.82 (s,
1H), 7.13-7.07 (m, 2H), 6.80 (s, 1H), 6.78-6.74 (m, 2H), 4.66-4.55
(m, 1H), 3.81 (s, 3H), 3.15 (d, 2H), 2.22 (s, 3H), 2.18-2.09 (m,
1H), 1.88-1.80 (m, 6H), 1.66-1.58 (m, 6H), 1.17-1.11 (m, 2H),
1.11-1.05 (m, 2H); LCMS: 444.1 [M+H].sup.+.
Step 2:
tert-Butyl-2-(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)(-
(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyc-
lohexyl)acetate
[0799] Intermediate 19.06 (5 mL in toluene, 0.701 mmol) was added
to a solution of
4-(2-cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.-
2]octan-1-yl)methyl)pyridin-2-amine (136 mg, 0.306 mmol), Et.sub.3N
(155 mg, 1.53 mmol), and CH.sub.2Cl.sub.2 (5 mL) at 0.degree. C.
The mixture was allowed to warm to rt, stirred for 1 h, poured into
H.sub.2O (50 mL), and then extracted with EtOAc (3.times.30 mL).
The combined organic layers were washed (100 mL brine), dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by silica gel chromatography (petroleum
ether/EtOAc=20/1.fwdarw.5/1) to give
tert-butyl-2-(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-m-
ethoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl-
)acetate (155 mg, 76%) as a colorless oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.50 (d, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.46
(d, 1H), 7.07-6.99 (m, 2H), 6.76-6.69 (m, 1H), 3.88-3.73 (m, 5H),
2.40-2.25 (m, 1H), 2.22-2.10 (m, 4H), 2.01-1.99 (m, 2H), 1.89-1.66
(m, 12H), 1.65-1.55 (m, 3H), 1.48-1.45 (m, 4H), 1.42 (s, 9H),
1.20-1.06 (m, 4H), 0.80-0.71 (m, 2H).
Step 3:
2-(trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-metho-
xy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)ace-
tic acid
[0800] Hydrogen chloride (8 M in dioxane, 100 mL, 800 mmol) was
added to a solution of
tert-butyl-2-(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-m-
ethoxy-3-methylphenyl)
bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)acetate (125
mg, 0.187 mmol) and dioxane (10 mL) at 5.degree. C. The mixture was
allowed to warm to rt, stirred for 1 h and then concentrated. The
residue was purified by RP-HPLC (water(0.05% HCl)/CH.sub.3CN) to
give
trans-2-(4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-me-
thylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)acetic
acid (43 mg, 38%) as a yellow solid. 1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.01(s, 1H), 8.76 (s, 1H), 8.52 (d, 1H),
7.74 (s, 1H), 7.63 (d, 1H), 7.05-6.94 (m, 2H), 6.76 (d, 1H),
3.81-3.62 (m, 5H), 2.30-2.14 (m, 2H), 2.08 (s, 3H), 1.99 (d, 2H),
1.78-1.51 (m, 11H), 1.48-1.24 (m, 8H), 1.13-1.05 (m, 2H), 1.05-0.99
(m, 2H), 0.70-0.67 (m, 2H); LCMS: 612.3[M+H].sup.+.
[0801] The following Compounds were synthesized from the
appropriate Intermediates following the procedures described for
Compound 21.
TABLE-US-00040 Cmpd Structure Name [M + H].sup.+ 21.01 ##STR01209##
2-(trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)acetic acid
586.5 21.02.sup.1,2 ##STR01210##
2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)acetic acid
585.5 21.03 ##STR01211## 2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclohexyl) acetic acid 586.5
21.04.sup.3 ##STR01212## 2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((cis-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclohexyl) acetic acid 586.6
21.05.sup.1 ##STR01213## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-(2- cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl)acetic acid 596.5 21.06.sup.1
##STR01214## 2-(trans-4-((3-(2-Cyclopropyloxazol-4-
yl)phenyl)((trans-4-(6- (dimethylamino)pyridin-3-
yl)cyclohexyl)methyl)carbamoyl)cyclohexyl) acetic acid 585.5
21.07.sup.1 ##STR01215## 2-(trans-4-((4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl)carbamoyl)cyclohexyl) acetic acid 587.5
21.08.sup.1 ##STR01216## 2-(trans-4-((3-(2-lsopropyloxazol-4-
yl)phenyl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)acetic acid
587.4 21.09.sup.1 ##STR01217## 2-(trans-4-((4-(2-Isopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)acetic acid
588.4 21.10.sup.1 ##STR01218## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(3-(2- isopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl)acetic acid 598.7 21.11 ##STR01219##
2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-(2-
isopropyloxazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl)acetic acid
599.4 21.12 ##STR01220## 2-(trans-4-(((trans-4-(3-Cyano-4-
methoxyphenyl)cyclohexyl)methyl)(4-(2-
cyclopropyloxazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl)acetic
acid 597.4 21.13.sup.1 ##STR01221##
2-(trans-4-(((trans-4-(6-Cyano-5-
methoxypyridin-2-yl)cyclohexyl)methyl)(3- (2-cyclopropyloxazol-4-
yl)phenyl)carbamoyl)cyclohexyl)acetic acid 597.4 Alternate
conditions: Step 2: .sup.1Base was pyridine; Step 3: .sup.212M aq.
HCl, CH.sub.3CN. .sup.3Cis isomer of Compound 21.03 (Step 2) was
separated by via prep-TLC (petroleum ether:EtOAc = 3:2) and then
hydrolyzed (4M HCl in dioxane, rt, 1 h).
Compound 22
trans-Propyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate
##STR01222##
[0803] A solution of Compound 17.13 (35 mg, 0.061 mmol),
pTsOH.H.sub.2O (10 mg, 0.053 mmol), and 1-propanol (4 mL) was
heated at 80.degree. C. for 4 h and then diluted with saturated
NaHCO.sub.3 (20 mL) and EtOAc (20 mL). The layers were separated,
and the organic phase was washed with brine (20 mL), dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
silica gel chromatography (0-50% EtOAc in hexanes) to give
trans-propyl
4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methyl-
phenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate as a
white foam (30 mg, 79%). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.38 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H),
7.44 (t, 1H), 7.10 (d, 1H), 6.97-6.92 (m, 2H), 6.80-6.75 (m, 1H),
3.88 (t, 2H), 3.77-3.72 (m, 1H), 3.71 (s, 3H), 3.67-3.40 (m, 2H),
2.38-2.28 (m, 1H), 2.26-2.17 (m, 1H), 2.16-2.09 (m, 1H), 2.08 (s,
3H), 1.85-1.65 (m, 8H), 1.56-1.47 (m, 2H), 1.46-1.37 (m, 3H),
1.35-1.21 (m, 2H), 1.11-1.02 (m, 4H), 1.01-0.92 (m, 4H), 0.81 (t,
3H); LCMS: 612.6 [M+H].sup.+.
[0804] The Compounds below were synthesized from Compound 17.13 or
Compound 18.17 and the appropriate alcohol following the procedure
described for Compound 22.
TABLE-US-00041 Cmpd Structure Name [M + H].sup.+ 22.01 ##STR01223##
trans-Isopropyl 4-((3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 612.6 22.02 ##STR01224## trans-Butyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 626.5 22.03 ##STR01225## trans-Pentyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 640.3 22.04 ##STR01226## trans-Isobutyl
4-((3-(1-cyclopropyl-1H- pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 626.6 22.05 ##STR01227## trans-Isopentyl
4-((3-(1-cyclopropyl- 1H-pyrazol-4-yl)phenyl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)
cyclohexanecarboxylate 640.6 22.06 ##STR01228## trans-Propyl
4-((4-(1-cyclopropyl-1H- pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-
methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)
cyclohexanecarboxylate 614.3
Compound 23
trans-N.sup.1-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N.sup.4-(2-hydroxy-
ethyl)-N.sup.1-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclo-
hexane-1,4-dicarboxamide
##STR01229##
[0806] 2-Aminoethanol (96.5 mg, 1.58 mmol) was added to a solution
of Compound 17.13 (150 mg, 0.263 mmol), EDCI (75.7 mg, 0.394 mmol),
DMAP (16.1 mg, 0.131 mmol), Et.sub.3N (79.8 mg, 0.790 mmol), HOBt
(53.4 mg, 0.395 mmol), and CH.sub.2Cl.sub.2 (1 mL) at 0.degree. C.
The mixture was stirred at rt overnight, poured into water (40 mL),
and extracted with EtOAc (3.times.50 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, concentrated,
and then purified by reverse-phase prep-HPLC (water(10 mM
NH.sub.4HCO.sub.3)/MeCN) to give
trans-M-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N.sup.4-(2-hydroxyethyl-
)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-1,4--
dicarboxamide (89 mg, 55%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.33 (s, 1H), 7.93 (s, 1H), 7.66-7.57 (m,
2H), 7.57-7.53 (m, 1H), 7.44 (t, 1H), 7.10 (d, 1H), 7.00-6.89 (m,
2H), 6.83-6.67 (m, 1H), 4.57 (t, 1H), 3.77-3.68 (m, 4H), 3.68-3.49
(m, 2H), 3.31-3.26 (m, 2H), 3.09-3.01 (m, 2H), 2.39-2.22 (m, 1H),
2.17-1.96 (m, 5H), 1.83-1.53 (m, 8H), 1.52-1.21 (m, 5H), 1.15-0.85
(m, 8H); LCMS: 613.3 [M+H].sup.+.
Compound 24
trans-N.sup.1-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-N.sup-
.1-(3-(2-methoxythiazol-5-yl)phenyl)-M-methylcyclohexane-1,4-dicarboxamide
##STR01230##
[0808] HATU (44 mg, 0.116 mmol) was added to a mixture of Compound
17.01 (60 mg, 0.104 mmol), iPr.sub.2NEt (36 .mu.L, 0.207 mmol), and
DMF (1 mL) at 0.degree. C. The mixture was stirred for 10 min, and
then methylamine (40% in CH.sub.3OH, 0.1 mL, 0.98 mmol) was added.
After stirring at 0.degree. C. for 10 min, the reaction was diluted
with CH.sub.2Cl.sub.2 (20 mL), washed (20 mL H.sub.2O and then 20
mL brine), dried (Na.sub.2SO.sub.4), and then concentrated. The
residue was purified by silica gel chromatography (0-5% CH.sub.3OH
in CH.sub.2Cl.sub.2) to give
trans-N.sup.1-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-
-(2-methoxythiazol-5-yl)phenyl)-N.sup.4-methylcyclohexane-1,4-dicarboxamid-
e (38 mg, 62%) as a white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.75 (s, 1H), 7.61-7.56 (m, 1H), 7.55-7.47
(m, 3H), 7.28-7.21 (m, 1H), 6.98-6.91 (m, 2H), 6.81-6.76 (m, 1H),
4.06 (s, 3H), 3.71 (s, 3H), 3.65-3.46 (m, 2H), 2.47 (d, 3H),
2.39-2.27 (m, 1H), 2.12-1.92 (m, 5H), 1.80-1.56 (m, 8H), 1.49-1.35
(m, 3H), 1.34-1.21 (m, 2H), 1.12-0.92 (m, 4H); LCMS: 590.4
[M+H].sup.+.
[0809] The Compounds below were synthesized from the appropriate
amine following the procedure described for Compound 24.
TABLE-US-00042 Cmpd Structure Name [M + H].sup.+ 24.01 ##STR01231##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.1- (3-(2-methoxythiazol-5-
yl)phenyl)cyclohexane-1,4- dicarboxamide 576.3 24.02 ##STR01232##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N.sup.1-
(3-(2-methoxythiazol-5-yl)phenyl)-
N.sup.4,N.sup.4-dimethylcyclohexane- 1,4-dicarboxamide 604.4 24.03
##STR01233## trans-N.sup.1-((2-Hydroxyethyl)-N.sup.4-((trans-
4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-
N.sup.4-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexane-1,4-
dicarboxamide 620.4 24.04 ##STR01234##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-
N.sup.4-(2-methoxyethyl)-N.sup.1-(3-(2- methoxythiazol-5-yl)phenyl)
cyclohexane-1,4-dicarboxamide 634.6 24.05 ##STR01235##
trans-N.sup.1-(2-(Dimethylamino)ethyl)-
N.sup.4-((trans-4-(4-methoxy-3- methylphenyl)cyc1ohexyl)methyl)-
N.sup.4-(3-(2-methoxythiazol-5- yl)phenyl)cyclohexane-1,4-
dicarboxamide 647.5 24.06.sup.1 ##STR01236##
trans-N.sup.1-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)- N.sup.1-(3-(2-methoxythiazol-5-yl)
phenyl)-N.sup.4-(methylsulfonyl) cyclohexane-1,4- dicarboxamide
654.4 Variation: .sup.1DBU was also added, rt, 30 min.
Compound 25
Methyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-
-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
##STR01237##
[0810] Step 1: tert-Butyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
[0811] Pyridine (0.17 mL, 2.10 mmol) and then Intermediate 19.02
(38.6 mg/mL in toluene, 8 mL, 1.18 mmol) were added to a mixture of
Intermediate 14.06 (227 mg, 0.53 mmol) and toluene (2 mL) under
N.sub.2 at rt. The reaction was stirred for 1 h, poured into sat'd
NaHCO.sub.3 (30 mL), and then extracted with EtOAc (30 mL). The
organics were washed with brine (30 mL). The combined aqueous
washes were back extracted with EtOAc (20 mL). The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, concentrated, and
purified by silica gel chromatography (20-50% EtOAc in hexanes) to
give tert-butyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (331 mg,
96%) as an off-white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.10 (s, 1H), 7.62-7.56 (m, 2H), 7.52 (t, 1H), 7.29-7.24
(m, 1H), 6.97-6.92 (m, 2H), 6.81-6.76 (m, 1H), 6.54 (d, 1H), 3.72
(s, 3H), 3.61-3.52 (m, 2H), 3.17-3.06 (m, 1H), 2.47-2.39 (m, 1H),
2.38-2.28 (m, 1H), 2.09 (s, 3H), 2.06-1.96 (m, 1H), 1.79-1.62 (m,
8H), 1.48-1.38 (m, 3H), 1.36-1.22 (m, 11H), 1.18-1.11 (m, 2H),
1.11-1.03 (m, 2H), 1.03-0.98 (m, 2H), 0.86-0.72 (m, 2H); LCMS:
680.8 [M+Na].sup.+.
Step 2:
trans-4-Amino-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4--
(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
[0812] A solution of tert-butyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (326 mg,
0.50 mmol) and trifluoroacetic acid (20% in CH.sub.2Cl.sub.2, 5 mL)
was stirred at rt for 2 h, diluted with CH.sub.2Cl.sub.2 (25 mL),
washed with sat'd NaHCO.sub.3 (2.times.30 mL), and then washed with
brine (30 mL). The combined aqueous washes were back extracted with
CH.sub.2Cl.sub.2 (20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, concentrated, and dried on high
vacuum to give
trans-4-amino-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (256
mg, 92%) as an off-white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.09 (s, 1H), 7.62-7.49 (m, 3H), 7.30-7.23 (m, 1H),
6.98-6.92 (m, 2H), 6.82-6.75 (m, 1H), 3.72 (s, 3H), 3.62-3.50 (m,
2H), 3.38-3.28 (m, 1H), 2.48-2.39 (m, 1H), 2.38-2.29 (m, 1H), 2.09
(s, 3H), 2.06-1.96 (m, 1H), 1.80-1.57 (m, 10H), 1.48-1.37 (m, 3H),
1.35-1.23 (m, 2H), 1.18-1.12 (m, 2H), 1.12-0.97 (m, 4H), 0.73-0.58
(m, 2H); LCMS: 558.5 [M+H].sup.+.
Step 3: Methyl
(trans-4-03-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-meth-
ylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
[0813] A solution of
trans-4-amino-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-meth-
oxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (100
mg, 0.18 mmol) in CH.sub.2Cl.sub.2 (2 mL) was cooled in an
ice/water bath under N.sub.2. Triethylamine (0.10 mL, 0.72 mmol)
and then methyl chloroformate (17 4, 0.22 mmoL) were added at
0.degree. C., and the reaction was stirred for 8 min. The mixture
was diluted with 20 mL CH.sub.2Cl.sub.2, washed with sat'd
NaHCO.sub.3 (2.times.20 mL), and washed with brine (20 mL). The
combined aqueous washes were back extracted with 20 mL
CH.sub.2Cl.sub.2. The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, concentrated, and purified by silica
gel chromatography (20-80% EtOAc in hexanes) to give methyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (92 mg,
83%) as an off-white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.09 (s, 1H), 7.61-7.56 (m, 2H), 7.52 (t, 1H), 7.27 (d,
1H), 6.97-6.92 (m, 2H), 6.87-6.75 (m, 2H), 3.71 (s, 3H), 3.62-3.51
(m, 2H), 3.45 (br s, 3H), 3.23-3.09 (m, 1H), 2.48-2.39 (m, 1H),
2.38-2.28 (m, 1H), 2.09 (s, 3H), 2.06-1.97 (m, 1H), 1.80-1.62 (m,
8H), 1.50-1.36 (m, 3H), 1.36-1.22 (m, 2H), 1.18-1.11 (m, 2H),
1.11-0.97 (m, 4H), 0.88-0.74 (m, 2H); LCMS: 616.4 [M+H].sup.+.
[0814] The Compounds below were synthesized from the appropriate
starting materials following the procedure described for Compound
25, Step 1.
TABLE-US-00043 Cmpd Structure Name [M + H].sup.+ 25.01 ##STR01238##
tert-Butyl (trans-4-(((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)(3-(2- methoxythiazol-5-
yl)phenyl)carbamoyl) cyclohexyl)carbamate 670.5 M + Na 25.02
##STR01239## tert-Butyl ((trans-4-(((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)(3-(2- methoxythiazol-5-
yl)phenyl)carbamoyl)cyclohexyl) methyl)carbamate 606.4 [(M - tBu +
H) + H].sup.+
[0815] The Compound below was synthesized from Compound 25.02
following the procedure described for Compound 25, Step 2.
TABLE-US-00044 Cmpd Structure Name [M + H].sup.+ 25.03.sup.1
##STR01240## trans-4-(Aminomethyl)-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)- N-(3-(2-methoxythiazol-5-
yl)phenyl)cyclohexanecarboxamide 562.4 Variation: .sup.10.degree.
C., 100 min.
[0816] The Compounds below were synthesized from the appropriate
amine and the appropriate acylating agent following the procedure
described for Compound 25.
TABLE-US-00045 Cmpd Structure Name [M + H].sup.+ 25.04.sup.1,3
##STR01241## trans-4-Acetamido-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)-N- (3-(2-methoxythiazol-5-
yl)phenyl)cyclohexanecarboxamide 590.5 25.05.sup.1.3 ##STR01242##
Methyl (trans-4-(((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl)(3- (2-methoxythiazol-5-
yl)phenyl)carbamoyl)cyclohexyl) carbamate 606.4 25.06.sup.2
##STR01243## trans-4-(Acetamidomethyl)-N-((trans- 4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-N- (3-(2-methoxythiazol-5-
yl)phenyl)cyclohexanecarboxamide 604.4 25.07 ##STR01244## Methyl
((trans-4-(((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl)(3-(2- methoxythiazol-5-
yl)phenyl)carbamoyl)cyclohexyl) methyl)carbamate 620.8 25.08
##STR01245## trans-N-((trans-4-(4-Methoxy-3-
methylphenyl)cyclohexyl)methyl)-N-
(3-(2-methoxythiazol-5-yl)phenyl)-4- (methylsulfonamidomethyl)
cyclohexanecarboxamide 640.5 25.09.sup.2,3 ##STR01246##
trans-4-Acetamido-N-(3-(2- cyclopropylthiazol-5-yl)phenyl)-N-
((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
cyclohexanecarboxamide 600.4 25.10.sup.5 ##STR01247##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (N-methylacetamido)
cyclohexanecarboxamide 614.6 25.11 ##STR01248##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (methylsulfonamido)
cyclohexanecarboxamide 636.4 25.12.sup.2 ##STR01249##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- methoxyacetamido)
cyclohexanecarboxamide 630.4 25.13.sup.2 ##STR01250##
2-((trans-4-((3-(2-Cyclopropylthiazol-
5-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl) amino)-2-oxoethyl acetate 658.6 25.14.sup.3
##STR01251## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-hydroxyacetamido)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 616.3
25.15.sup.6 ##STR01252## 2-((trans-4-((3-(2-Cyclopropylthiazol-
5-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl) amino)-2-oxoethyl methylcarbamate 673.5
25.16.sup.1 ##STR01253## trans-4-Butyramido-N-(3-(2-
cyclopropylthiazol-5-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclo hexanecarboxamide 628.5
25.17.sup.1 ##STR01254## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-
pentanamidocyclohexanecarboxamide 642.4 25.18.sup.1 ##STR01255##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- methylbutanamido)
cyclohexanecarboxamide 642.5 Alternate conditions: Step 3:
.sup.1Base was pyridine; .sup.2Solvent was EtOAc; .sup.3rt, 0.5-3
h. .sup.4From Compound 25.13 (1M NaOH, THF CH.sub.3OH, rt).
.sup.5From Compound 25.09 (NaH, THF, CH.sub.3I, 0.degree. C.-rt).
.sup.6From Compound 25.14 (procedure for Compound 2).
Compound 26
Methyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-met-
hoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
##STR01256##
[0817] Step 1: tert-Butyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
[0818] Pyridine (0.17 mL, 2.10 mmol) and then Intermediate 19.02
(38.6 mg/mL in toluene, 8 mL, 1.18 mmol) were added to a solution
of Intermediate 14.22 (223 mg, 0.537 mmol) in toluene (2 mL) at rt.
The resulting mixture was stirred at rt for 55 min, poured into 30
mL sat'd NaHCO.sub.3 and then extracted with 30 mL EtOAc. The
organic layer was washed with 30 mL brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and purified by silica
gel chromatography (30-60% EtOAc in hexanes) to give tert-butyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (328
mg, 95%) as a white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.57-7.52 (m,
1H), 7.44 (t, 1H), 7.10 (d, 1H), 6.98-6.92 (m, 2H), 6.81-6.76 (m,
1H), 6.54 (d, 1H), 3.78-3.69 (m, 4H), 3.64-3.46 (m, 1H), 3.17-3.04
(m, 1H), 2.38-2.28 (m, 1H), 2.12-2.00 (m, 4H), 1.81-1.60 (m, 8H),
1.50-1.22 (m, 15H), 1.12-0.95 (m, 6H), 0.85-0.70 (m, 2H); LCMS:
663.7 [M+Na].sup.+.
Step 2:
trans-4-Amino-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((tran-
s-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
[0819] A solution of tert-butyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (321
mg, 0.50 mmol) and trifluoroacetic acid (20% in CH.sub.2Cl.sub.2, 5
mL) was stirred at rt for 2 h, diluted with 25 mL CH.sub.2Cl.sub.2,
washed with sat'd NaHCO.sub.3 (2.times.30 mL), and then washed with
30 mL brine. The combined aqueous layers were back extracted with
20 mL CH.sub.2Cl.sub.2. The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give
trans-4-amino-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(267 mg, 98%) as an off-white foam. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H),
7.56-7.52 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.97-6.93 (m, 2H),
6.80-6.76 (m, 1H), 3.77-3.69 (m, 4H), 3.64-3.47 (m, 2H), 3.11-2.87
(m, 1H), 2.47-2.38 (m, 1H), 2.38-2.28 (m, 1H), 2.26-2.13 (m, 1H),
2.11-2.00 (m, 4H), 1.80-1.70 (m, 4H), 1.70-1.58 (m, 4H), 1.48-1.37
(m, 3H), 1.35-1.22 (m, 2H), 1.12-0.95 (m, 6H), 0.72-0.59 (m, 2H);
LCMS: 541.6 [M+H].sup.+.
Step 3: Methyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
[0820] Triethylamine (0.13 mL, 0.74 mmol) and then methyl
chloroformate (17 .mu.L, 0.22 mmol) were added to a solution of
trans-4-amino-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4--
methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide
(100 mg, 0.19 mmol) in CH.sub.2Cl.sub.2 (2 mL) at 0.degree. C.
under Na. The reaction was stirred at 0.degree. C. for 13 min,
diluted with 20 mL CH.sub.2Cl.sub.2, washed with sat'd NaHCO.sub.3
(2.times.20 mL), and then washed with brine (20 mL). The combined
aqueous washes were back extracted with 20 mL CH.sub.2Cl.sub.2. The
combined extracts were dried (Na.sub.2SO.sub.4), filtered,
concentrated, and purified by silica gel chromatography (40-90%
EtOAc in hexanes) to give methyl
(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (88
mg, 79%) as a white foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.57-7.53 (m,
1H), 7.44 (t, 1H), 7.10 (d, 1H), 6.97-6.92 (m, 2H), 6.87-6.81 (m,
1H), 6.81-6.76 (m, 1H), 3.77-3.69 (m, 4H), 3.65-3.38 (m, 5H),
3.22-3.09 (m, 1H), 2.38-2.28 (m, 1H), 2.11-2.00 (m, 4H), 1.80-1.62
(m, 8H), 1.49-1.35 (m, 3H), 1.35-1.22 (m, 2H), 1.11-0.95 (m, 6H),
0.87-0.73 (m, 2H); LCMS: 599.4 [M+H].sup.+.
[0821] The Compounds below were synthesized from Intermediate 14.22
and the appropriate acylating agent following the procedures
described for Compound 26.
TABLE-US-00046 Cmpd Structure Name [M + H].sup.+ 26.01.sup.1
##STR01257## trans-4-Acetamido-N-(3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
583.5 26.02 ##STR01258## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (methylsulfonamido)
cyclohexanecarboxamide 619.5 26.03.sup.2,6 ##STR01259##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)-4-(2-hydroxyacetamido)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 599.5
26.04.sup.3 ##STR01260## 2-((trans-4-((3-(1-Cyclopropyl-1H-
pyrazol-4-yl)phenyl)((trans-4-(4- methoxy-3-methylphenyl)
cyclohexyl)methyl) carbamoyl)cyclohexyl)amino)- 2-oxoethyl
methylcarbamate 656.6 26.05.sup.4 ##STR01261## 2-Hydroxyethyl
(trans-4-((3-(1- cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)carbamate 629.3 26.06.sup.5 ##STR01262##
trans-N-(3-(1-Cyclopropyl-1H- pyrazol-4-yl)phenyl)-4-(trans-4-
hydroxycyclohexanecarboxamido)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 667.6
Alternate conditions: Step 3: .sup.1Ac.sub.2O, Et.sub.3N, EtOAc,
rt; .sup.2Solvent was EtOAc. .sup.3From Compound 26.03 (procedure
for Compound 2). .sup.4From Intermediate 20 (Et.sub.3N,
CH.sub.2Cl.sub.2, rt, overnight). .sup.5From Intermediate 19, then
desilylation (1N HCl, THF, CH.sub.3OH, 0.degree. C.-rt, 75 min).
.sup.6From acetoxyacetyl chloride, then hydrolysis (1M NaOH, THF,
CH.sub.3OH, rt).
[0822] The Compounds below were synthesized from the appropriate
Intermediate and the appropriate acylating agents following the
procedures described for Compound 26.
TABLE-US-00047 Cmpd Structure Name [M + H].sup.+ 26.07.sup.1,4,6
##STR01263## trans-4-Acetamido-N-(3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)-N-((4-(4- methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)cyclohexanecarboxamide 609.5 26.08.sup.1,6 ##STR01264##
2-((4-((3-(1-Cyclopropyl-1H-pyrazol-4- yl)phenyl)((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)carbamoyl)cyclohexyl)amino)- 2-oxoethyl trans-acetate
667.6 26.09.sup.7 ##STR01265##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-4-(2-hydroxyacetamido)- N-((4-(4-methoxy-3-
methylphenyl)bicyclo[2.2.2]octan-1-
yl)methyl)cyclohexanecarboxamide 625.4 26.10.sup.1,4,6 ##STR01266##
trans-4-Acetamido-N-(3-(1-isopropyl-
1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4- methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 585.5
26.11.sup.1,6 ##STR01267## 2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)
methyl)carbamoyl) cyclohexyl)amino)-2-oxoethyl acetate 643.5
26.12.sup.7 ##STR01268## trans-4-(2-Hydroxyacetamido)-N-(3-(1-
isopropyl-1H-pyrazol-4-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 601.5
26.13.sup.1,5 ##STR01269## trans-4-(Acetamidomethyl)-N-(3-(1-
cyclopropyl-1H-pyrazol-4-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 597.3
26.14.sup.1,5 ##STR01270## Methyl ((trans-4-((3-(1-cyclopropyl-
1H-pyrazol-4-yl)phenyl)((trans-4-(4- methoxy-3-methylphenyl)
cyclohexyl)methyl) carbamoyl)cyclohexyl) methyl)carbamate 613.6
26.15.sup.1,5 ##STR01271## trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (methylsulfonamidomethyl)
cyclohexanecarboxamide 633.5 26.16.sup.1,7 ##STR01272##
trans-N-(3-(2-Cyclopropyloxazol-4-
yl)phenyl)-4-(2-hydroxyacetamido)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 600.4
26.17.sup.2,6 ##STR01273## 2-((trans-4-((4-(2-cyclopropyloxazol-
4-yl)pyridine-2-yl)((trans-4-(4- methoxy-3-methylphenyl)
cyclohexyl)methyl) carbamoyl)cyclohexyl)amino)- 2-oxoethyl acetate
643.6 26.18.sup.7 ##STR01274## trans-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)-4-(2- hydroxyacetamido)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 601.4
26.19.sup.1,4 ##STR01275## trans-4-Acetamido-N-(3-(2-
cyclopropyloxazol-4-yl)phenyl)-N- ((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 584.5
26.20.sup.2,4,6 ##STR01276## trans-4-Acetamido-N-(4-(2-
cyclopropyloxazol-4-yl)pyridine- 2-yl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 585.5
26.21.sup.3 ##STR01277## Methyl (trans-4-((4-(2- cyclopropyloxazol-
4-yl)pyridine-2-yl)((trans-4- (5-methoxy-
6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)
cyclohexyl)carbamate 602.4 26.22.sup.3,8 ##STR01278##
trans-4-(Aminomethyl)-N-(4-(2-
cyclopropyloxazol-4-yl)pyridin-2-yl)- N-((trans-4-(5-methoxy-6-
methylpyridin-2- yl)cyclohexyl)methyl) cyclohexanecarboxamide 558.5
Alternate conditions: Step 1: .sup.1Solvent was CH.sub.2Cl.sub.2;
.sup.2DMAP, pyridine, 80.degree. C.; .sup.3DMAP, Et.sub.3N,
toluene, 80.degree. C.; Step 3: .sup.4Ac.sub.2O; .sup.5Base was
pyridine; .sup.6Solvent was EtOAc. .sup.7From hydrolysis of
acetylated Compound (1M NaOH, THF CH.sub.3OH, rt). .sup.8Steps 1
& 2 only.
[0823] The Compounds below were synthesized from Compound 4.16 or
Compound 26.22 following the procedure described for Compound 26,
Step 3.
TABLE-US-00048 Cmpd Structure Name [M + H].sup.+ 26.23.sup.1
##STR01279## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2-acetamidoethyl)carbamate 670.5 26.24.sup.2
##STR01280## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl (2- (methylsulfonamido)ethyl)carbamate 706.6
26.25 ##STR01281## trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl methyl ethane-1,2- diyldicarbamate 686.8 26.26
##STR01282## trans-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl)-4- (methylsulfonamidomethyl)
cyclohexanecarboxamide 636.6 26.27 ##STR01283## Methyl
((trans-4-((4-(2-cyclopropyloxazol-
4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)
cyclohexyl)methyl)carbamate 616.6 26.28 ##STR01284## Ethyl
((trans-4-(4-(2-cyclopropyloxazol-4-
yl)pyridin-2-yl)((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)
cyclohexyl)methyl)carbamate 630.6 26.29.sup.3 ##STR01285##
trans-N-(4-(2-Cyclopropyloxazol-4- yl)pyridin-2-yl)-4-((2-
hydroxyacetamido)methyl)-N-((trans-4-(5- methoxy-6-methylpyridin-2-
yl)cyclohexyl)methyl) cyclohexanecarboxamide 616.5 Step 3:
.sup.1Ac.sub.2O, Et.sub.3N, EtOAc, rt; .sup.2Solvent was EtOAc.
.sup.3From acetoxyacetyl chloride then hydrolysis (1M NaOH, THF
CH.sub.3OH, rt).
[0824] The Compounds below were synthesized from Intermediate 23.07
or Intermediate 23.08 following the procedures described for
Compound 26, Steps 2 & 3.
TABLE-US-00049 Cmpd Structure Name [M + H].sup.+ 26.30.sup.1
##STR01286## trans-4-Acetamido-N-(4-(1-cyclopropyl-
1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-
(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 584.5 26.31 ##STR01287##
2-((trans-4-(4-(1-Cyclopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl)
methyl)carbamoyl)cyclohexyl)amino)- 2-oxoethyl acetate 642.6
26.32.sup.2 ##STR01288## trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-
yl)pyridin-2-yl)-4-(2-hydroxyacetamido)- N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 600.4
26.33.sup.1 ##STR01289## trans-4-Acetamido-N-(4-(1-isopropyl-1H-
pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
586.5 26.34 ##STR01290## 2-((trans-4-((4-(1-Isopropyl-1H-pyrazol-
4-yl)pyridin-2-yl)((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)amino)-
2-oxoethyl acetate 644.6 26.35.sup.2 ##STR01291##
trans-4-(2-Hydroxyacetamido)-N-(4-(1-
isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-
N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 602.5 Step 3: .sup.1Ac.sub.2O, Et.sub.3N,
CH.sub.2Cl.sub.2, rt. .sup.2From hydrolysis of acetylated Compound
(1M NaOH, THF CH.sub.3OH, rt).
[0825] The Compounds below were synthesized from Compound 25, Step
2 or Compound 26, Step 2 following the procedure described for
Compound 5 using methylamine (40% in CH.sub.3OH).
TABLE-US-00050 Cmpd Structure Name [M + H].sup.+ 26.36 ##STR01292##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3-
methylureido)cyclohexanecarboxamide 615.5 26.37 ##STR01293##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3-
methylureido)cyclohexanecarboxamide 598.5
Compound 27
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxy-2-methylpropana-
mido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanec-
arboxamide
##STR01294##
[0827]
((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphoniu-
m hexafluorophosphate(V) (229.9 mg, 0.442 mmol) and iPr.sub.2NEt
(0.804 mmol, 0.14 mL) were added to a solution of Compound 25, Step
2 (205.4 mg, 0.368 mmol), 2-hydroxy-2-methylpropanoic acid (46.1
mg, 0.442 mmol) and DMF (2 mL) at 0.degree. C. under N.sub.2. The
reaction was stirred at rt overnight, poured into water (30 mL),
and then extracted with EtOAc (3.times.20 mL). The organic layers
were combined, washed with brine (2.times.20 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated, and then purified by
reverse-phase HPLC (water(10 mM NH.sub.4HCO.sub.3)/CH.sub.3CN) to
give
trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxy-2-methylpropan-
amido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-
carboxamide (76.8 mg, 32%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.09 (s, 1H), 7.63-7.56 (m, 2H), 7.55-7.47
(m, 1H), 7.27 (d, 1H), 7.21 (d, 1H), 6.98-6.91 (m, 2H), 6.78-6.76
(m, 1H), 5.17 (s, 1H), 3.71 (s, 3H), 3.55-3.49 (m, 2H), 3.42-3.40
(m, 1H), 2.47-2.39 (m, 1H), 2.33 (t, 1H), 2.08-2.03 (m, 4H),
1.80-1.57 (m, 8H), 1.51-1.37 (m, 3H), 1.35-1.22 (m, 2H), 1.19-1.11
(m, 8H), 1.11-0.90 (m, 6H); LCMS: 644.3 [M+H].sup.+.
[0828] The Compounds below were synthesized from Compound 25, Step
2 and the appropriate acid following the procedure described for
Compound 27.
TABLE-US-00051 Cmpd Structure Name [M + H].sup.+ 27.01 ##STR01295##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-hydroxypropanamido)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 630.4 27.02 ##STR01296##
N-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)oxetane-3- carboxamide 642.5 27.03
##STR01297## trans-4-(2-(1H-Imidazol-1-yl)acetamido)-
N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-
N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)
methyl)cyclohexanecarboxamide 666.5 27.04 ##STR01298##
trans-4-(2-(1H-Imidazol-2-yl)acetamido)-
N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-
N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)
methyl)cyclohexanecarboxamide 666.6 27.05 ##STR01299##
N-(trans-4-((3-(2-Cyclopropylthiazol-5-
yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl)cyclohexyl)-1- methylazetidine- 3-carboxamide 655.5
27.06.sup.1 ##STR01300## N-(trans-4-((3-(2-Cyclopropylthiazol-
5-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)
carbamoyl) cyclohexyl)azetidine-3-carboxamide 641.5 .sup.1From
1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid after
deprotection (TFA/CH.sub.2Cl.sub.2).
Compound 28
2-Hydroxyethyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate
##STR01301##
[0830] Potassium carbonate (148.6 mg, 1.07 mmol) was added to a
solution of Compound 25, Step 2 (200 mg, 0.358 mmol) and
1,3-dioxolan-2-one (94.7 mg, 1.08 mmol) in DMF (5 mL) at rt. The
mixture was heated at 120.degree. C. overnight under N.sub.2,
poured into water (50 mL), and extracted with EtOAc (3.times.50
mL). The organic layers were combined, dried over Na.sub.2SO.sub.4,
filtered, concentrated, and then purified by reverse-phase HPLC
(water(10 mM NH.sub.4HCO.sub.3)-MeCN) to give 2-hydroxyethyl
(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (19 mg,
8%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.09 (s, 1H), 7.48-7.63 (m, 3H), 7.27 (d, 1H), 6.94-6.86 (m, 3H),
6.79-6.738 (m, 1H), 4.69-4.63 (m, 1H), 3.89-3.83 (m, 2H), 3.72 (s,
3H), 3.70-3.49 (m, 4H), 3.19-3.12 (m, 1H), 2.34-2.33 (m, 1H),
2.15-1.96 (m, 4H), 1.85-1.55 (m, 9H), 1.48-1.38 (m, 3H), 1.37-1.27
(d, 2H), 1.18-0.97 (m, 6H), 0.93-0.81( m, 2H); LCMS: 646.3
[M+H].sup.+.
Compound 29
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetic
Acid
##STR01302##
[0831] Step 1:
Ethyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetate
[0832] Ethyl-2-bromoacetate (257.2 mg, 1.54 mmol) was added to a
solution of Compound 26.10, Step 2 (380 mg, 0.7 mmol), Et.sub.3N
(0.22 mL, 1.54 mmol), and CH.sub.2Cl.sub.2 (5 mL). The reaction was
stirred at rt overnight, concentrated, and then purified by silica
gel chromatography (petroleum ether/EtOAc/EtOH=4/3/1). The compound
was further purified by reverse-phase HPLC (water(0.05% HCl)/MeCN)
to give
ethyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetate
(65.5 mg, 15%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.32 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H),
7.55-7.51 (m, 1H), 7.43 (t, 1H), 7.12-7.02 (m, 1H), 6.98-6.90 (m,
2H), 6.82-6.73 (m, 1H), 4.58-4.42 (m, 1H), 4.04 (q, 2H), 3.71 (s,
3H), 3.64-3.44 (m, 2H), 3.38-3.32 (m, 4H), 2.40-2.21 (m, 1H),
2.15-2.00 (m, 4H), 1.83-1.58 (m, 8H), 1.48-1.41 (m, 7H), 1.40-1.22
(m, 4H), 1.11 (t, 3H), 1.07-0.96 (m, 2H), 0.70-0.51 (m, 2H); LCMS:
629.5 [M+H].sup.+.
Step 2:
2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetic
Acid
[0833] Lithium hydroxide monohydrate (53.4 mg, 1.27 mmol) was added
to a solution of
ethyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-me-
thoxy-3-methylphenyl)cyclohexyl)methypcarbamoyl)cyclohexyl)amino)acetate
(100 mg, 0.16 mmol), THF (4 mL), and H.sub.2O (1 mL) at 0.degree.
C. The reaction was allowed to warm to rt and stirred overnight.
The resulting solution was concentrated at rt to remove most of the
THF, diluted with H.sub.2O (10 mL), and then further concentrated
until 5 mL of H.sub.2O was removed. The mixture was cooled to
0.degree. C. and 1 M HCl was added dropwise under vigorous stirring
(to avoid clumping) to pH=6. The solid was filtered, washed with
ice H.sub.2O (20 mL), and then dried on high vacuum to give
2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetic
acid (70 mg, 73%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.34 (s, 1H), 7.95 (s, 1H), 7.61 (d, 1H),
7.56 (s, 1H), 7.45 (t, 1H), 7.14-7.05 (m, 1H), 7.02-6.87 (m, 2H),
6.83-6.70 (m, 1H), 4.59-4.42 (m, 1H), 3.85-3.55 (m, 5H), 3.15-3.01
(m, 2H), 2.88-2.72 (m, 1H), 2.40-2.27 (m, 1H), 2.21-2.03 (m, 4H),
2.01-1.85 (m, 2H), 1.85-1.65 (m, 6H), 1.53-1.24 (m, 11H), 1.15-0.86
(m, 4H); LCMS: 601.4 [M+H].sup.+.
Compound 30
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)-4-(3-methoxycyclobutanecarboxamido)cycloh-
exanecarboxamide
##STR01303##
[0835] A mixture of Compound 26, Step 2 (80 mg, 0.15 mmol),
3-methoxycyclobutane carboxylic acid (30 mg, 0.23 mmol), EDCI (47
mg, 0.24 mmol), iPr.sub.2NEt (89 .mu.L, 0.51 mmol) and
dichloromethane (0.8 mL) was stirred at rt for 4 h and then diluted
with EtOAc (10 mL). The organics were washed with water (10 mL),
washed with brine (10 mL), dried (Na.sub.2SO.sub.4), filtered,
concentrated and then purified by silica gel chromatography (0-10%
methanol in dichloromethane) to give
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(3-methoxycyclobutanecarboxamido)cyclo-
hexanecarboxamide as a pale yellow foam (77 mg, 79% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.34 (s, 1H), 7.93 (s, 1H),
7.59 (d, 1H), 7.54 (s, 1H), 7.44 (t, 1H), 7.40 (d, 1H), 7.10 (d,
1H), 6.97-6.92 (m, 2H), 6.78 (d, 1H), 3.77-3.69 (m, 4H), 3.69-3.60
(m, 1H), 3.60-3.49 (m, 2H), 3.46-3.35 (m, 1H), 3.07 (s, 3H),
2.38-2.25 (m, 2H), 2.23-2.14 (m, 2H), 2.11-2.01 (m, 4H), 1.89-1.80
(m, 2H), 1.80-1.61 (m, 8H), 1.48-1.36 (m, 3H), 1.36-1.22 (m, 2H),
1.11-0.95 (m, 6H), 0.84-0.70 (m, 2H); LCMS: 653.6 [M+H].sup.+.
[0836] The Compound below was synthesized from the appropriate
amine and the appropriate acid following the procedure described
for Compound 30.
TABLE-US-00052 Cmpd Structure Name [M + H].sup.+ 30.01 ##STR01304##
trans-4-(Cyclobutanecarboxamido)-N-(3-
(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-
N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 623.5 30.02 ##STR01305##
trans-4-(cyclobutanecarboxamido)-trans-(4-
(2-cyclopropyloxazol-4-yl)pyridine-2-yl)-N-
((trans-4-(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)
cyclohexanecarboxamide 626.5 30.03 ##STR01306##
trans-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)-N-((trans-4-(5-methoxy-6-
methylpyridin-2-yl)cyclohexyl)methyl)-4-
(3-methoxycyclobutanecarboxamido) cyclohexanecarboxamide 656.7
30.04 ##STR01307## trans-4-(Cyclobutanecarboxamidomethyl)-
N-(4-(2-cyclopropyloxazol-4-yl)
pyridin-2-yl)-N-((trans-4-(5-methoxy-6- methylpyridin-2-
yl)cyclohexyl)methyl) cyclohexanecarboxamide 640.6 30.05
##STR01308## trans-N-(4-(2-Cyclopropyloxazol-4-
yl)pyridin-2-yl)-4-((3-(dimethylamino)
cyclobutanecarboxamido)methyl)-N-
((trans-4-(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)
cyclohexanecarboxamide 683.4 30.06.sup.1 ##STR01309##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfonamido)acetamido)
cyclohexanecarboxamide 693.3 .sup.1EDCI, HOBt, iPr.sub.2NEt, DMF,
0.degree. C.-rt, overnight.
Compound 31
Methyl
(2-((trans-4-((03-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(-
4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-o-
xoethyl)carbamate
##STR01310##
[0838] Triethylamine (449.1 mg, 4.44 mmol) was added to a solution
of Compound 26, Step 2 (200 mg, 0.37 mmol) and
2-((methoxycarbonyl)amino)acetic acid (147.7 mg, 1.11 mmol) in DMF
(3 mL) under Na at 0.degree. C. Then
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(942 mg, 1.48 mmol, 50% purity) was added dropwise at 0.degree. C.
The mixture was allowed to warm to rt and stirred overnight. The
mixture was poured into H.sub.2O (40 mL) and then extracted with
EtOAc (3.times.50 mL). The combined organic layers were washed with
brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated,
and then purified by reverse-phase prep-HPLC (water(10 mM
NH.sub.4HCO.sub.3)/MeCN) to give methyl
(2-((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(-
4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-o-
xoethyl)carbamate (35.1 mg, 14%) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d,
1H), 7.55 (s, 1H), 7.51-7.41 (m, 2H), 7.18-7.08 (m, 2H), 6.97-6.92
(m, 2H), 6.81-6.74 (m, 1H), 3.78-3.69 (m, 4H), 3.65-3.52 (m, 2H),
3.49 (s, 3H), 3.46-3.38 (m, 3H), 2.38-2.28 (m, 1H), 2.12-2.03 (m,
4H), 1.81-1.62 (m, 8H), 1.50-1.37 (m, 3H), 1.35-1.22 (m, 2H),
1.12-0.95 (m, 6H), 0.91-0.77 (m, 2H); LCMS: 656.3 [M+H].sup.+.
[0839] The Compounds below were synthesized from Compound 26, Step
2 or Compound 25, Step 2 and the appropriate acids following the
procedure described for Compound 31.
TABLE-US-00053 Cmpd Structure Name [M + H].sup.+ 31.01 ##STR01311##
trans-4-(2-Acetamidoacetamido)-N-(3-(1-
cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)
methyl)cyclohexanecarboxamide 640.6 31.02 ##STR01312##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfonypacetamido)
cyclohexanecarboxamide 661.3 31.03 ##STR01313##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfonamido)acetamido)
cyclohexane carboxamide 676.6 31.04.sup.1 ##STR01314##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfinyl)acetamido)
cyclohexanecarboxamide 645.3 31.05 ##STR01315## Methyl
(2-((trans-4-((3-(2- cyclopropylthiazol-5-yl)phenyl)((trans-
4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
carbamoyl)cyclohexyl)amino)- 2-oxoethyl)carbamate 673.3 31.06
##STR01316## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-(dimethylamino)
acetamido)-N-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)
methyl)cyclohexanecarboxamide 643.4 31.07.sup.3 ##STR01317##
trans-4-(2-Aminoacetamido)-N-(3-(2-
cyclopropylthiazol-5-yl)phenyl)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 615.4 31.08.sup.3 ##STR01318##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylamino)acetamido)
cyclohexanecarboxamide 629.5 31.09 ##STR01319##
trans-4-(2-Acetamidoacetamido)-N- (3-(2-cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy- 3-methylphenyl)cyclohexyl)
methyl)cyclohexanecarboxamide 657.4 31.10 ##STR01320##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4- (2-(methylthio)acetamido)
cyclohexanecarboxamide 646.6 31.11.sup.2 ##STR01321##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfinyl)acetamido)
cyclohexanecarboxamide 662.5 31.12 ##STR01322##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2- (methylsulfonyl)acetamido)
cyclohexanecarboxamide 678.5 31.13.sup.1 ##STR01323##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- (methylsulfinyl)propanamido)
cyclohexanecarboxamide 676.2 31.14 ##STR01324##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(3- (methylsulfonyl)propanamido)
cyclohexanecarboxamide 692.5 31.15 ##STR01325##
trans-4-(2-(1H-Imidazol-4-yl)acetamido)-
N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-
N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 666.5 .sup.1From oxidation of sulfide
(NaOI.sub.4, THF/H.sub.2O, 0.degree. C-rt, overnight). .sup.2From
Compound 31.10 (m-CPBA, CH.sub.2Cl.sub.2, 0.degree. C.-rt, 2 h).
.sup.3After removal of Boc (HCl/EtOAc).
Compound 32
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)a-
cetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohex-
anecarboxamide
##STR01326##
[0840] Step 1:
trans-4-(2-Chloroacetamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-
-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxam-
ide
[0841] A solution of Compound 26, Step 2 (500 mg, 0.924 mmol) and
pyridine (789.9 mg, 9.99 mmol) in CH.sub.2Cl.sub.2 (5 mL) was
degassed and purged with N.sub.2 3 times at 0.degree. C.
2-Chloroacetyl chloride (313.3 mg, 2.77 mmol) was added. The
mixture was allowed to warm to rt and stirred for 2 h under
N.sub.2. The mixture was poured into water (60 mL) and extracted
with EtOAc (3.times.40 mL). The organic layer was combined, dried
over Na.sub.2SO.sub.4, filtered, concentrated, and then purified by
prep-TLC (SiO.sub.2, CH.sub.2Cl.sub.2/CH.sub.3OH=10/1) to give
trans-4-(2-chloroacetamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-
-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxam-
ide (400 mg, 70%) as a black brown solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.75 (d, 2H), 7.51-7.40 (m, 2H), 7.29-7.24 (m,
1H), 7.04 (d, 1H), 6.99-6.93 (m, 2H), 6.74 (d, 1H), 6.23 (d, 1H),
3.98 (s, 2H), 3.80 (s, 3H), 3.78-3.71 (m, 1H), 3.70-3.57 (m, 3H),
2.46-2.34 (m, 1H), 2.25-2.11 (m, 4H), 2.07-1.92 (m, 2H), 1.92-1.68
(m, 8H), 1.43-1.28 (m, 2H), 1.27-1.05 (m, 7H), 1.03-0.87 (m, 2H);
LCMS: 617.2 [M+H].sup.+.
Step 2:
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxyp-
ropoxy)acetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-
cyclohexanecarboxamide
[0842] Sodium hydride (12.2 mg, 0.303 mmol, 60% purity) was added
to a solution of propane-1,3-diol (31.4 mg, 0.413 mmol) in DMF (5
mL) at 0.degree. C. under N.sub.2. After 30 min at 0.degree. C.,
trans-4-(2-chloroacetamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-
-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxam-
ide (170 mg, 0.275 mmol) was added, and the reaction was allowed to
stir at rt overnight. The mixture was poured into water (30 mL) and
extracted with EtOAc (3.times.50 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, concentrated, and then
purified by reverse-phase HPLC (water(10 mM
NH.sub.4HCO.sub.3)/MeCN) to give
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)-
acetamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohe-
xanecarboxamide (18.1 mg, 10%) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.33 (s, 1H), 7.93 (s, 1H), 7.59 (d,
1H), 7.54 (s, 1H), 7.44 (t, 1 H), 7.37 (d, 1H), 7.10 (d, 1H),
7.01-6.88 (m, 2H), 6.84-6.68 (m, 1H), 4.45-4.41 (m, 1H), 3.81-3.71
(m, 5H), 3.64-3.45 (m, 3H), 3.45-3.39 (m, 5H), 2.39-2.26 (m, 1H),
2.12-2.01 (m, 4H), 1.84-1.54 (m, 10H), 1.52-1.35 (m, 3H), 1.33-1.21
(m, 2H), 1.14-0.85 (m, 8H); LCMS: 657.4 [M+H].sup.+.
[0843] The Compounds below were synthesized from the appropriate
starting materials following the procedures described for Compound
32.
TABLE-US-00054 Cmpd Structure Name [M + H].sup.+ 32.01 ##STR01327##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol- 4-yl)phenyl)-4-(2-(2-
hydroxyethoxy)acetamido)-N-((trans-4-
(4-methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
643.8 32.02 ##STR01328## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-(2-hydroxyethoxy) acetamido)-N-((trans-4-(4-
methoxy-3-methylphenyl) cyclohexyl)methyl) cyclohexanecarboxamide
660.6 32.03 ##STR01329## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-(3-hydroxypropoxy) acetamido)-N-((trans-4-(4-
methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide
674.5 32.04 ##STR01330## trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-4-(2-(2-(dimethylamino)ethoxy)
acetamido)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 687.6
32.05.sup.1 ##STR01331## trans-4-(2-(2-Aminoethoxy)acetamido)-N-
(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-
((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)
cyclohexanecarboxamide 659.5 32.06 ##STR01332##
trans-N-(3-(2-Cyclopropylthiazol-5-
yl)phenyl)-N-((trans-4-(4-methoxy-3-
methylphenyl)cyclohexyl)methyl)-4-(2-(2-
(methylamino)ethoxy)acetamido) cyclohexanecarboxamide 673.5
.sup.1From Boc-protected amino alcohol (NaOH, TBAI, toluene,
80.degree. C.; then TFA/CH.sub.2Cl.sub.2, rt, 3 h).
Compound 33
trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-met-
hylphenyl)cyclohexyl)methyl)-4-(2H-tetrazol-5-yl)cyclohexanecarboxamide
##STR01333##
[0845] A solution of Intermediate 21.21 (345 mg, 0.607 mmol), TMSN3
(700 mg, 6.08 mmol), dibutylstannanone (75.63 mg, 0.303 mmol) and
toluene (25 mL) was heated at 120.degree. C. overnight under
N.sub.2, allowed to cool to rt, and then concentrated to dryness.
The crude product was purified by reverse-phase prep-HPLC
(water(0.05%HCl))/CH.sub.3CN) to give
trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-me-
thylphenyl)cyclohexyl)methyl)-4-(2H-tetrazol-5-yl)cyclohexanecarboxamide
(108.2 mg, 29%) as a white solid. .sup.1H NMR (400 MHz, CD3OD):
.delta. 7.99 (s, 1H), 7.69 (d, 1H), 7.63-7.56 (m, 2H), 7.34 (d,
1H), 7.01-6.91 (m, 2H), 6.77 (d, 1H), 3.78 (s, 3H), 3.76-3.60 (m,
2H), 3.09-2.96 (m, 1H), 2.47-2.32 (m, 3H), 2.15 (s, 3H), 2.07 (d,
2H), 1.98-1.82 (m, 6H), 1.81-1.68 (m, 2H), 1.64-1.51 (m, 1H),
1.49-1.30 (m, 4H), 1.30-1.17 (m, 4H), 1.14-1.08 (m, 2H); LCMS:
611.3 [M+H].sup.+.
[0846] The Compound below was synthesized from Intermediate 21.23
following the procedure described for Compound 33.
TABLE-US-00055 Cmpd Structure Name [M + H].sup.+ 33.01 ##STR01334##
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-
4-yl)phenyl)-N-((trans-4-(4-methoxy-
3-methylphenyl)cyclohexyl)methyl)-4- (2H-tetrazol-5-yl)
cyclohexanecarboxamide 594.3
Compound 34
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-
-methylphenyl)cyclohexyl)methyl)-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl-
)cyclohexanecarboxamide
##STR01335##
[0847] Step 1:
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-((Z)-N'-hydroxycarbam-
imidoyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexa-
necarboxamide
[0848] Hydroxylamine hydrochloride (1.21 g, 17.43 mmol) in water (5
mL) was added dropwise to a solution of sodium carbonate (1.54 g,
18.30 mmol) in water (25 mL). This mixture was added to a solution
of Intermediate 21.23 (240 mg, 0.435 mmol) in EtOH (10 mL). The
mixture was heated at 80.degree. C., stirred overnight, and then
allowed to cool to rt. The organic solvent was removed from the
mixture. The aqueous layer was extracted with 1-PrOH/CHCl.sub.2
(1:3; 3.times.20 mL). The combined layers were washed with water (5
mL), washed with brine (5 mL), dried over Na.sub.2SO.sub.4,
filtered, concentrated, and then purified by prep-TLC (SiO2, 100%
EtOAc) to give
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-((Z)-N-hydroxycarbami-
midoyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexan-
ecarboxamide (200 mg, 79%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.60 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H),
7.60 (d, 1H), 7.54 (s, 1H), 7.44 (t, 1H), 7.10 (d, 1H), 7.00-6.90
(m, 2H), 6.81-6.74 (m, 1H), 5.19 (s, 2H), 3.82-3.69 (m, 4H),
3.66-3.45 (m, 2H), 3.31-3.28 (m, 1H), 2.38-2.29 (m, 1H), 2.18-2.12
(m, 1H), 2.09 (s, 3H), 1.92-1.85 (m, 1H), 1.78-1.60 (m, 7H),
1.50-1.37 (m, 3H), 1.35-1.20 (m, 3H), 1.10-1.05 (m, 4H), 1.04-0.95
(m, 3H); LCMS: 584.3 [M+H].sup.+.
Step 2:
trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-m-
ethoxy-3-methylphenyl)cyclohexyl)methyl)-4-(5-oxo-4,5-dihydro-1,2,4-oxadia-
zol-3-yl)cyclohexanecarboxamide
[0849] A mixture of
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-((Z)-N-hydroxycarbami-
midoyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexan-
ecarboxamide (200 mg, 0.342 mmol), CDI (83.3 mg, 0.513 mmol) and
dioxane (2 mL) was stirred at 100.degree. C. for 0.5 h, and then
allowed to cool to rt. The mixture was poured into water (40 mL)
and extracted with EtOAc (3.times.5 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, concentrated,
and then purified by prep-TLC (SiO2, 100% EtOAc) to give
trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy--
3-methylphenyl)cyclohexyl)methyl)-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-y-
l)cyclohexanecarboxamide (42.5 mg, 20%) as a white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 11.98 (s, 1H), 8.34 (s, 1H),
7.94 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.47-7.43 (m, 1H), 7.12
(d, 1H), 6.99-6.90 (m, 2H), 6.81-6.74 (m, 1H), 3.78-3.68 (m, 4H),
3.67-3.46 (m, 2H), 2.57-2.51 (m, 1H), 2.36-2.31 (m, 1H), 2.2-2.15
(m, 1H), 2.09 (s, 3H), 1.86-1.69 (m, 8H), 1.58-1.37 (m, 3H),
1.36-1.21 (m, 3H), 1.12-1.04 (m, 5H), 1.02-0.96 (m, 2H); LCMS:
610.4 [M+H].sup.+.
EXAMPLE A-1
Parenteral Pharmaceutical Composition
[0850] To prepare a parenteral pharmaceutical composition suitable
for administration by injection (subcutaneous, intravenous), 1-1000
mg of a compound described herein, or a pharmaceutically acceptable
salt or solvate thereof, is dissolved in sterile water and then
mixed with 10 mL of 0.9% sterile saline. A suitable buffer is
optionally added as well as optional acid or base to adjust the pH.
The mixture is incorporated into a dosage unit form suitable for
administration by injection
EXAMPLE A-2
Oral Solution
[0851] To prepare a pharmaceutical composition for oral delivery, a
sufficient amount of a compound described herein, or a
pharmaceutically acceptable salt thereof, is added to water (with
optional solubilizer(s), optional buffer(s) and taste masking
excipients) to provide a 20 mg/mL solution.
EXAMPLE A-3
Oral Tablet
[0852] A tablet is prepared by mixing 20-50% by weight of a
compound described herein, or a pharmaceutically acceptable salt
thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by
weight of low-substituted hydroxypropyl cellulose, and 1-10% by
weight of magnesium stearate or other appropriate excipients.
Tablets are prepared by direct compression. The total weight of the
compressed tablets is maintained at 100-500 mg.
EXAMPLE A-4
Oral Capsule
[0853] To prepare a pharmaceutical composition for oral delivery,
10-500 mg of a compound described herein, or a pharmaceutically
acceptable salt thereof, is mixed with starch or other suitable
powder blend. The mixture is incorporated into an oral dosage unit
such as a hard gelatin capsule, which is suitable for oral
administration.
[0854] In another embodiment, 10-500 mg of a compound described
herein, or a pharmaceutically acceptable salt thereof, is placed
into Size 4 capsule, or size 1 capsule (hypromellose or hard
gelatin) and the capsule is closed.
EXAMPLE A-5
Topical Gel Composition
[0855] To prepare a pharmaceutical topical gel composition, a
compound described herein, or a pharmaceutically acceptable salt
thereof, is mixed with hydroxypropyl celluose, propylene glycol,
isopropyl myristate and purified alcohol USP. The resulting gel
mixture is then incorporated into containers, such as tubes, which
are suitable for topical administration.
EXAMPLE B-1
In Vitro FXR Assay (TK)
Seeding
[0856] CV-1 cells were seeded at a density of 2,000,000 cells in a
T175 flask with DMEM+10% charcoal double-stripped FBS and incubated
at 37.degree. C. in 5% CO.sub.2 for 18 h (O/N).
Transfection
[0857] After 18 h of incubation, the medium in the T175 flask was
changed with fresh DMEM+10% charcoal super-stripped serum. In a
polypropylene tube, 2500 .mu.L OptiMEM (Life Technologies, Cat
#31985-062) was combined with expression plasmids for hFXR, hRXR,
TK-ECRE-luc and pCMX-YFP. The tube was then briefly vortexed and
incubated at room temperature for 5 minutes. Transfection reagent
(X-tremeGENE HP from Roche, Cat #06 366 236 001) was added to the
OptiMEM/plasmid mixture vortexed and incubated at room temperature
for 20 minutes. Following incubation, the transfection reagent/DNA
mixture complex was added to cells in the T175 flask and the cells
were incubated at 37.degree. C. in 5% CO.sub.2 for 18 h (O/N).
Test Compounds
[0858] Compounds were serially diluted in DMSO and added to
transfected CV-1 cells. The cells were then incubated for 18 hrs.
The next day cells were lysed and examined for luminescence.
[0859] Representative data for exemplary compounds disclosed herein
is presented in the following table.
TABLE-US-00056 TABLE 3 TK hFXR: Compound No EC.sub.50 (uM) 1 +++
1.01 +++ 1.02 +++ 1.03 +++ 1.04 +++ 1.05 +++ 1.06 +++ 1.07 +++ 1.08
+++ 1.09 +++ 1.10 +++ 2 +++ 2.01 +++ 2.02 +++ 2.03 +++ 2.04 +++
2.05 +++ 2.06 +++ 2.07 +++ 2.08 +++ 3 +++ 3.01 +++ 3.02 +++ 3.03
+++ 3.04 +++ 3.05 +++ 4 +++ 4.01 +++ 4.02 +++ 4.03 +++ 4.04 +++
4.05 +++ 4.06 +++ 4.07 +++ 4.08 +++ 4.09 +++ 4.10 +++ 4.11 +++ 4.12
+++ 4.13 +++ 4.14 +++ 4.15 +++ 4.16 +++ 4.17 +++ 4.18 +++ 4.19 +++
4.20 +++ 4.21 +++ 4.22 +++ 4.23 +++ 4.24 +++ 4.25 +++ 4.26 +++ 4.27
+++ 4.28 +++ 5 +++ 5.01 +++ 5.02 +++ 5.03 +++ 5.04 +++ 5.05 +++
5.06 +++ 5.07 +++ 5.08 +++ 5.09 +++ 5.10 +++ 5.11 +++ 5.12 +++ 5.13
+++ 5.14 +++ 5.15 +++ 5.16 +++ 5.17 +++ 5.18 +++ 5.19 +++ 5.20 +++
5.21 +++ 5.22 +++ 5.23 +++ 5.24 +++ 5.25 +++ 5.26 +++ 5.27 +++ 5.28
+++ 5.29 +++ 5.30 +++ 5.31 +++ 5.32 +++ 5.33 +++ 5.34 +++ 5.35 +++
5.36 +++ 5.37 +++ 5.38 +++ 5.39 +++ 5.40 +++ 5.41 +++ 5.42 +++ 5.43
+++ 5.44 +++ 5.45 +++ 5.46 +++ 5.47 +++ 5.48 +++ 5.49 +++ 5.50 +++
5.51 +++ 5.52 +++ 5.53 +++ 6 +++ 6.01 +++ 6.02 +++ 6.03 +++ 6.04
+++ 6.05 +++ 6.06 +++ 6.07 +++ 6.08 +++ 6.09 +++ 6.10 +++ 6.11 +++
6.12 +++ 6.13 +++ 6.14 +++ 6.15 +++ 6.16 +++ 6.17 +++ 6.18 +++ 6.19
+++ 6.20 +++ 6.21 +++ 6.22 +++ 6.23 +++ 6.24 +++ 6.25 +++ 6.26 +++
6.27 +++ 6.28 +++ 6.29 +++ 6.30 +++ 6.31 +++ 6.32 +++ 6.33 +++ 6.34
+++ 6.35 +++ 6.36 +++ 6.37 +++ 6.38 +++ 6.39 +++ 6.40 +++ 6.41 +++
6.42 +++ 6.43 +++ 6.44 +++ 6.45 +++ 6.46 +++ 6.47 +++ 6.48 +++ 6.49
+++ 6.50 +++ 6.51 +++ 6.52 +++ 6.53 +++ 6.54 +++ 6.55 +++ 6.56 +++
6.57 +++ 6.58 +++ 6.59 +++ 6.60 +++ 6.61 +++ 6.62 +++ 6.63 +++ 6.64
+++ 6.65 +++ 6.66 ++ 6.67 +++ 6.68 +++ 6.69 +++ 6.70 +++ 6.71 +++
6.72 +++ 6.73 +++ 6.74 +++ 6.75 +++ 6.76 +++ 6.77 +++ 6.78 ++ 6.79
+++ 6.80 +++ 6.81 +++ 6.82 +++ 6.83 +++ 6.84 +++ 6.85 +++ 6.86 +++
6.87 +++ 6.88 +++ 6.89 +++ 6.90 +++ 6.91 +++ 6.92 +++ 6.93 +++ 6.94
+++ 6.95 +++ 6.96 +++ 7 +++ 7.01 +++ 7.02 +++ 7.03 +++ 7.04 +++
7.05 +++ 7.06 +++ 7.07 +++ 7.08 +++ 7.09 +++ 7.10 +++ 7.11 +++ 7.12
+++ 7.13 +++ 7.14 +++ 7.15 +++ 7.16 +++ 7.17 +++ 7.18 +++ 7.19 +++
7.20 +++ 7.21 +++ 7.22 +++ 7.23 +++ 7.24 +++ 7.25 +++ 7.26 +++ 7.27
+++ 7.28 +++ 7.29 +++ 7.30 +++ 7.31 +++ 7.32 +++ 7.33 +++ 7.34 +++
7.35 +++ 7.36 +++ 7.37 +++
7.38 +++ 7.39 +++ 7.40 +++ 7.41 +++ 7.42 +++ 7.43 +++ 7.44 +++ 7.45
+++ 7.46 +++ 7.47 +++ 7.48 +++ 7.49 +++ 7.50 +++ 7.51 +++ 7.52 +++
7.53 +++ 7.54 +++ 7.55 +++ 7.56 +++ 7.57 +++ 7.58 +++ 7.59 +++ 7.60
+++ 7.61 +++ 7.62 +++ 7.63 +++ 7.64 +++ 7.65 +++ 7.66 +++ 7.67 +++
7.68 +++ 7.69 +++ 7.70 +++ 7.71 +++ 7.72 +++ 7.73 +++ 7.74 +++ 7.75
+++ 7.76 +++ 7.77 +++ 7.78 +++ 7.79 +++ 7.80 +++ 7.81 +++ 7.82 +++
7.83 +++ 7.84 +++ 7.85 +++ 7.86 ++ 7.87 +++ 7.88 +++ 7.89 +++ 7.90
+++ 7.91 +++ 7.92 +++ 7.93 +++ 7.94 +++ 7.95 +++ 7.96 ++ 7.97 +++
7.98 +++ 7.99 +++ 7.100 +++ 7.101 +++ 7.102 +++ 7.103 +++ 7.104 +++
7.105 +++ 7.106 +++ 7.107 +++ 7.108 +++ 7.109 +++ 8 +++ 8.01 +++ 9
+++ 10 +++ 11 ++ 12 +++ 13 +++ 13.01 +++ 13.02 +++ 13.03 +++ 13.04
+++ 13.05 ++ 14 +++ 15 +++ 15.01 +++ 15.02 +++ 15.03 +++ 15.04 +++
16 +++ 17 +++ 17.01 +++ 17.02 +++ 17.03 +++ 17.04 +++ 17.05 +++
17.06 +++ 17.07 +++ 17.08 +++ 17.09 +++ 17.10 ++ 17.11 +++ 17.12
+++ 17.13 +++ 17.14 +++ 17.15 +++ 17.16 +++ 17.17 +++ 17.18 ++
17.19 +++ 17.20 +++ 17.21 + 17.22 +++ 17.23 ++ 17.24 +++ 17.25 +++
17.26 +++ 17.27 + 18 +++ 18.01 +++ 18.02 +++ 18.03 +++ 18.04 +++
18.05 +++ 18.06 +++ 18.07 +++ 18.08 +++ 18.09 +++ 18.10 +++ 18.11 +
18.12 + 18.13 +++ 18.14 +++ 18.15 +++ 18.16 +++ 18.17 ++ 18.18 +++
18.19 +++ 18.20 +++ 18.21 +++ 18.22 +++ 18.23 +++ 18.24 +++ 19 +++
20 +++ 20.01 +++ 20.02 +++ 20.03 +++ 20.04 +++ 20.05 +++ 20.06 +++
20.07 +++ 20.08 +++ 20.09 +++ 20.10 +++ 20.11 +++ 20.12 +++ 20.13
+++ 20.14 +++ 20.15 +++ 20.16 +++ 21 +++ 21.01 +++ 21.02 +++ 21.03
+++ 21.04 + 21.05 +++ 21.06 +++ 21.07 +++ 21.08 +++ 21.09 +++ 21.10
+++ 21.11 +++ 21.12 +++ 21.13 +++ 22 +++ 22.01 +++ 22.02 +++ 22.03
+ 22.04 +++ 22.05 ++ 22.06 ++ 23 ++ 24 +++ 24.01 +++ 24.02 +++
24.03 +++ 24.04 +++ 24.05 ++ 24.06 +++ 25 +++ 25.01 ++ 25.02 ++
25.03 + 25.04 +++ 25.05 +++ 25.06 +++ 25.07 +++ 25.08 +++ 25.09 +++
25.10 +++ 25.11 +++ 25.12 +++ 25.13 +++ 25.14 +++ 25.15 +++ 25.16
+++ 25.17 +++ 25.18 +++ 26 +++ 26.01 +++ 26.02 +++ 26.03 +++ 26.04
+++ 26.05 +++ 26.06 +++ 26.07 +++ 26.08 +++ 26.09 +++ 26.10 +++
26.11 +++ 26.12 +++ 26.13 +++ 26.14 +++ 26.15 +++ 26.16 +++ 26.17
+++ 26.18 +++ 26.19 +++ 26.20 +++ 26.21 +++ 26.22 + 26.23 +++ 26.24
+++ 26.25 +++ 26.26 +++ 26.27 +++ 26.28 +++ 26.29 ++ 26.30 +++
26.31 +++ 26.32 +++ 26.33 +++ 26.34 +++ 26.35 +++ 26.36 +++ 26.37
+++ 27 +++ 27.01 +++ 27.02 +++
27.03 ++ 27.04 +++ 27.05 + 27.06 + 28 +++ 29 + 30 +++ 30.01 +++
30.02 +++ 30.03 +++ 30.04 +++ 30.05 + 30.06 +++ 31 +++ 31.01 +
31.02 ++ 31.03 + 31.04 ++ 31.05 +++ 31.06 +++ 31.07 ++ 31.08 +++
31.09 +++ 31.10 +++ 31.11 +++ 31.12 +++ 31.13 ++ 31.14 +++ 31.15
+++ 32 +++ 32.01 +++ 32.02 +++ 32.03 +++ 32.04 +++ 32.05 ++ 32.06 +
33 +++ 33.01 +++ 34 +++ Where `+++` means EC.sub.50 .ltoreq. 0.25
uM; `++` means EC.sub.50 .gtoreq. 0.25 uM & <1 uM; `+` means
EC.sub.50 .gtoreq. 1 uM. Compounds with a maximum efficacy of
<25% of the Fexarmine control were classified as `+`.
EXAMPLE B-2
In Vitro FXR Assay (hSHP)
Seeding
[0860] CV-1 cells were seeded at a density of 2,000,000 cells in a
T175 flask with DMEM+10% charcoal double-stripped FBS and incubated
at 37.degree. C. in 5% CO.sub.2 for 18 h (O/N).
Transfection
[0861] After 18 h of incubation, the medium in the T175 flask was
changed with fresh DMEM+10% charcoal super-stripped serum. In a
polypropylene tube, 2500 .mu.L OptiMEM (Life Technologies, Cat
#31985-062) was combined with expression plasmids for hFXR, hRXR,
hSHP-luc and pCMX-YFP. The tube was then briefly vortexed and
incubated at room temperature for 5 minutes. Transfection reagent
(X-tremeGENE HP from Roche, Cat #06 366 236 001) was added to the
OptiMEM/plasmid mixture vortexed and incubated at room temperature
for 20 minutes. Following incubation, the transfection reagent/DNA
mixture complex was added to cells in the T175 flask and the cells
were incubated at 37.degree. C. in 5% CO.sub.2 for 18 h (O/N).
Test Compounds
[0862] Compounds were serially diluted in DMSO and added to
transfected CV-1 cells. The cells were then incubated for 18 hrs.
The next day cells were lysed and examined for luminescence.
EXAMPLE B-3
NASH Activity Study (STZ Model)
[0863] NASH can be induced in male C57BL/6 by a single subcutaneous
injection of 200 ug STZ 2 days after birth followed by feeding high
fat diet (HFD) ad libitum after 4 weeks of age. While continuing
HFD, compounds can be dosed for 4-8 weeks to determine the effects
on NASH. Fasting glucose can be measured throughout the study with
a hand-held glucose meter. Serum alanine aminotransferase (ALT),
aspartate aminotransferase (AST) and triglyceride (TG) can be
measured by a clinical chemistry analyzer. The contents of TG in
the liver tissue can be measured using the Triglyceride E-test kit
(Wako, Tokyo, Japan). Histological analysis of liver sections can
be performed on tissue embedded in Tissue-TEK O.C.T. compound, snap
frozen in liquid nitrogen, and stored at -80 C. The sections can be
cut (5 um), air dried and fixed in acetone. For hematoxylin and
eosin staining, liver sections can be prefixed by Bouin's solution
and then stained with hematoxylin and eosin solution. The degree of
(zone-3) liver fibrosis can be assessed with Sirius red
staining.
EXAMPLE B-4
NASH Activity Study (AMLN model)
[0864] NASH is induced in male C57BL/6 mice by diet-induction with
AMLN diet (DIO-NASH) (D09100301, Research Diet, USA) (40% fat (18%
trans-fat), 40% carbohydrates (20% fructose) and 2% cholesterol).
The animals are kept on the diet for 29 weeks. After 26 weeks of
diet induction, liver biopsies are performed for base line
histological assessment of disease progression (hepatosteatosis and
fibrosis), stratified and randomized into treatment groups
according to liver fibrosis stage, steatosis score, and body
weight. Three weeks after biopsy the mice are stratified into
treatment groups and dosed daily by oral gavage with FXR agonists
for 8 weeks. At the end of the study liver biopsies are performed
to assess hepatic steatosis and fibrosis by examining tissue
sections stained with H&E and Sirius Red, respectively. Total
collagen content in the liver is measured by colorimetric
determination of hydroxyproline residues by acid hydrolysis of
collagen. Triglycerides and total cholesterol content in liver
homogenates are measured in single determinations using
autoanalyzer Cobas C-111 with commercial kit (Roche Diagnostics,
Germany) according to manufacturer's instructions.
EXAMPLE B-5
CCl.sub.4 Fibrosis Model
[0865] Fibrosis can be induced in BALB/c male mice by bi-weekly
administration of CCl.sub.4 administered by intraperitoneal
injection. CCl.sub.4 is formulated 1:1 in oil and is injected IP at
1 mL/kg. After 2-4 weeks of fibrosis induction the compounds can be
administered daily by oral gavage for 2-6 weeks of treatment while
continuing CCl.sub.4 administration. At study termination livers
can be formalin fixed and stained with Sirius Red stain for
histopathological evaluation of fibrosis. Total collagen content
can be measured by colorimetric determination of hydroxyproline
residues by acid hydrolysis of collagen. Serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) can be
measured by a clinical chemistry analyzer.
EXAMPLE B-6
Intrahepatic Cholestasis Model
[0866] Experimental intrahepatic cholestasis induced by
17a-ethynylestradiol (EE2) treatment in rodents is a widely used in
vivo model to examine the mechanisms involved in estrogen-induced
cholestasis. Intrahepatic cholestasis can be induced in adult male
mice by subcutaneous injection of 10 mg/kg 17a-ethynylestradiol
(E2) daily for 5 days. Testing of FXR ligands can be performed by
administration of compounds during E2 induction of cholestasis.
Cholestatic effects can be quantitated by assessing liver/body
weight ratio and measuring serum total bile acids and alkaline
phosphatase levels can be measured using reagents and controls from
Diagnostic Chemicals Ltd. and the Cobas Mira plus CC analyzer
(Roche Diagnostics). For histology and mitosis measurements, liver
samples from each mouse can be fixed in 10% neutral buffered
formalin. Slides are stained with hematoxylin and eosin using
standard protocols and examined microscopically for structural
changes. Hepatocyte proliferation is evaluated by
immunohistochemical staining for Ki67.
EXAMPLE B-7
Direct Target Gene Regulation
[0867] Direct target gene regulation by FXR ligands can be assessed
by dosing mice either acutely or chronically with compounds and
collecting tissues at various time points after dosing. RNA can be
isolated from tissues such as the ileum and liver, and reverse
transcribed to cDNA for quantitative PCR analysis of genes known in
the literature to be directly and indirectly regulated by FXR such
as SHP, BSEP, IBABP, FGF15, CYP7A1, CYP8B1 and C3.
EXAMPLE B-8
Mouse PK Study
[0868] The plasma pharmacokinetics of any one of the compounds
disclosed herein as a test article test article is measured
following a single bolus intravenous and oral administration to
mice (CD-1, C57BL, and diet induced obesity mice). Test article is
formulated for intravenous administration in a vehicle solution of
DMSO, PEG400, hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) and is
administered (for example at a dose volume of 3 mL/kg) at selected
dose levels. An oral dosing formulation is prepared in appropriate
oral dosing vehicles (vegetable oils, PEG400, Solutol, citrate
buffer, or carboxymethyl cellulose) and is administered at a dose
volume of 5-10 mL/kg at selected dose levels. Blood samples
(approximately 0.15 mL) are collected by cheek pouch method at
pre-determined time intervals post intravenous or oral doses into
tubes containing EDTA. Plasma is isolated by centrifugation of
blood at 10,000 g for 5 minutes, and aliquots are transferred into
a 96-well plate and stored at -60.degree. C. or below until
analysis.
[0869] Calibration standards of test article are prepared by
diluting DMSO stock solution with DMSO in a concentration range.
Aliquots of calibration standards in DMSO are combined with plasma
from naive mouse so that the final concentrations of calibration
standards in plasma are 10-fold lower than the calibration
standards in DMSO. PK plasma samples are combined with blank DMSO
to match the matrix. The calibration standards and PK samples are
combined with ice-cold acetonitrile containing an analytical
internal standard and centrifuged at 1850 g for 30 minutes at
4.degree. C. The supernatant fractions are analyzed by LC/MS/MS and
quantitated against the calibration curve. Pharmacokinetic
parameters (area under the curve (AUC), C.sub.max, T.sub.max,
elimination half-life (T.sub.1/2), clearance (CL), steady state
volume of distribution (V.sub.dss), and mean residence time (MRT))
are calculated via non-compartmental analysis using Microsoft Excel
(version 2013).
EXAMPLE B-9
Rat ANIT Model
[0870] A compound described herein is evaluated in a chronic
treatment model of cholestasis over a range of doses (for example,
doses in the range of 0.01 to 100 mg/kg). This model is used to
evaluate the suitability of the use of FXR agonists, e.g. a
compound described herein, for the treatment of cholestatic liver
disorders such as bile acid malabsorption (e.g., primary or
secondary bile acid diarrhea), bile reflux gastritis, collagenous
colitis, lymphocytic colitis, diversion colitis, indeterminate
colitis, Alagille syndrome, biliary atresia, ductopenic liver
transplant rejection, bone marrow or stem cell transplant
associated graft versus host disease, cystic fibrosis liver
disease, and parenteral nutrition-associated liver disease.
[0871] Rats are treated with alpha-naphthylisothiocyanate (ANIT)
(0.1% w/w) in food for 3 days prior to treatment with a compound
described herein, at a range of doses (for example, doses in the
range of 0.01 to 100 mg/kg). A noncholestatic control group is fed
standard chow diet without ANIT and serves as the noncholestatic
control animals ("Control"). After 14 days of oral dosing, rat
serum is analyzed for levels of analytes. LLQ, lower limit of
quantitation. Mean.+-.SEM; n=5.
[0872] Levels of hepatobiliary injury indicators are measured in
rat serum, such as elevated levels of circulating aspartate
aminotransferase (AST), alanine aminotransferase (ALT), bilirubin
and bile acids. ANIT exposure induces profound cholestasis and
hepatocellular damage. A compound that improves many of these
indicators is useful in the treatment of the aforementioned
diseases or conditions.
[0873] Reductions in the accumulation of bile acids in the liver,
enhancements in bile acid excretion in the biliary tract and
inhibition of bile acid synthesis is consistent with the
pharmacological action of a FXR agonist. An improvement in the
serum conjugated bilirubin (a direct indicator for hepatic
function) implies recovery from cholestasis with improved bile
excretion.
[0874] Furthermore, an analysis is made to ascertain the effects of
the compound described herein on serum FGF15 fibroblast growth
factor 15 (FGF15 in rodent; FGF19 in human) expression, a hormone
that is secreted in the portal blood and signals to the liver to
repress CYP7A1 expression synergistically with SHP. The direct
FXR-dependent induction of FGF15/19 along with FGF15/19's
anti-cholestatic properties makes it a convenient serum biomarker
for detecting target engagement of FXR agonists.
[0875] Serum FGF15 levels are quantified using an FGF15 Meso Scale
Discovery (MSD) assay. For example, Mouse FGF15 antibody from
R&D Systems (AF6755) is used both as capture and detection
antibody in the assay. MSD SULFO-TAG NHS-Ester is used to label the
FGF15 antibody. MSD standard 96-well plates are coated with the
FGF15 capture antibody and the plates are blocked with MSD Blocker
A (R93AA-2). After washing the plate with PBS+0.05% Tween 20, MSD
diluent 4 is dispensed into each well and incubated for 30 min. 25
pi of calibrator dilutions or samples (serum or EDTA plasma) are
dispensed into each well and incubated with shaking at RT.
[0876] After washing, detection antibody is added and incubated
with shaking for 1 h at RT. After washing and the addition of MSD
Read buffer (R92TC-2), the plate is read on an MSD SECTOR Imager
6000. Plots of the standard curve and unknown samples are
calculated using MSD data analysis software.
[0877] The examples and embodiments described herein are for
illustrative purposes only and various modifications or changes
suggested to persons skilled in the art are to be included within
the spirit and purview of this application and scope of the
appended claims.
EXAMPLE B-10
Mouse Chronic DSS Colitis Model
[0878] The chronic Dextran Sodium Sulfate (DSS)-induced mouse can
be used to test the therapeutic potential of compounds against
inflammatory bowel disease (IBD). Chronic colitis can be induced by
feeding mice DSS in drinking water. For example, 2% DSS in drinking
water for 5 days and regular drinking water for 5 days, then this
feeding cycle can be repeated two more times with higher
concentrations of DSS, 2.5% and 3%, respectively for a total of
three cycles. Colitis develops approximately after the first cycle
of DSS feeding, which can be monitored by loss of body weight,
stool consistency and rectal bleeding. An FXR agonist can be tested
by administering to mice at the same time of starting 2% DSS water
feeding. Alternatively, testing of an FXR agonist can be performed
post the first feeding cycle of 2% DSS water and regular water.
During the period of administering the FXR agonist to mice, the
therapeutic effects can be monitored by observations on body
weights, stool consistency and rectal bleeding. After euthanasia,
the disease development and effects of the FXR agonist can be
further quantified by measuring colon weight and length, colon
histology by H&E staining for inflammation and structural
changes in mucosa, and protein and RNA expression of genes related
to the disease.
EXAMPLE B-11
Adoptive T-cell Transfer Colitis Mouse Model
[0879] The adoptive T-cell transfer colitis model is accepted as a
relevant mouse model for human inflammatory bowel disease (IBD). To
induce colitis in this model, the CD4 T-lymphocyte population is
isolated from the spleens of donor mice, subsequently a
subpopulation of CD4+CD45RB high T-cells is purified by cell
sorting using flow cytometry. The purified CD4+CD45RB high T-cells
are injected into the peritoneal cavity of the recipient SCID mice.
Colitis develops approximately three to six weeks after T-cell
transfer, which can be monitored by loss of body weight (although
loss of body weight can be variable), inconsistent stool or bloody
diarrhea. Testing of an FXR agonist can be initiated at the same
time of injecting purified CD4+CD45RB high T-cells to the recipient
SCID mice. Alternatively, the FXR agonist can be administered two
or three weeks post T-cell transfer, when colitis has already
developed in the model. During the period of administering the FXR
agonist to mice, the therapeutic effects can be monitored by
observations on body weights, stool consistency and rectal
bleeding. After euthanasia, the disease development and effects of
the FXR agonist can be further quantified by measuring colon weight
and length, colon and ileum histology by H&E staining for
inflammation and structural changes in mucosa, and protein and RNA
expression of genes related to the disease.
EXAMPLE B-12
Mdr1a-/- Mouse Model
[0880] The Mdr1a-/- mouse model is a spontaneous colitis model that
has been used in testing new therapies for human IBD. Loss of the
Mdr1a gene in this model leads to impaired intestinal barrier
function, which results in increased infiltration of gut bacteria
and subsequent colitis. Under proper housing conditions, Mdr1a-/-
mice can develop colitis at about 8 to 13 weeks of age. During
disease progression, a disease activity index (DAI) summing the
clinical observation scores on rectal prolapse, stool consistency
and rectal bleeding can be used to monitor the disease. Testing of
an FXR agonist can be started at the initial stage of disease,
generally with DAI score less than 1.0. Alternatively,
administration of an FXR agonist can be initiated when colitis has
developed, typically with a DAI score above 2.0. Therapeutic
effects of the FXR agonist can be monitored by measuring the DAI,
and testing can be terminated when desired disease severity has
been achieved, generally with a DAI score around 5.0. After
euthanasia, the disease development and effects of the FXR agonist
can be further quantified by measuring colon weight and length,
colon histology by H&E staining for inflammation and structural
changes in mucosa, and protein and RNA expression of genes related
to the disease.
[0881] The examples and embodiments described herein are for
illustrative purposes only and various modifications or changes
suggested to persons skilled in the art are to be included within
the spirit and purview of this application and scope of the
appended claims.
* * * * *